#Receptor Gamma Coactivator 1-alpha (PGC-1α)

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Mitochondrial Dysfunction in Cardiovascular Disease

 Introduction

Mitochondria are essential organelles responsible for the production of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). The heart, due to its continuous contractile activity, has a high energy demand and is critically dependent on mitochondrial function for normal physiological and pathological processes. Mitochondrial dysfunction has emerged as a central mechanism in the pathogenesis of cardiovascular diseases (CVDs), including ischemic heart disease, heart failure, hypertension, and arrhythmias. This technical overview discusses the molecular mechanisms of mitochondrial dysfunction in cardiovascular disease, its impact on cellular and organ function, and the potential therapeutic strategies to mitigate mitochondrial-related pathophysiology in CVDs.

Mitochondrial Function in Cardiovascular Cells

Mitochondria are highly dynamic organelles that perform several key functions crucial for the health of cardiovascular cells. They are involved in:

ATP Production via Oxidative Phosphorylation: In the mitochondria, energy production is driven by the electron transport chain (ETC), which is composed of complex I-IV embedded in the inner mitochondrial membrane. Electrons derived from NADH and FADH2 produced during the citric acid cycle are transferred through these complexes to ultimately reduce oxygen to water at complex IV. This electron transfer drives proton pumps that create an electrochemical gradient (proton motive force) across the inner mitochondrial membrane, which is utilized by ATP synthase (complex V) to produce ATP.

Calcium Homeostasis: Mitochondria play a crucial role in buffering intracellular calcium concentrations. They take up calcium from the cytoplasm in response to cellular signaling and help maintain cellular homeostasis by storing calcium in the matrix and releasing it when required for cellular signaling. Dysregulation of mitochondrial calcium handling can lead to pathophysiological conditions such as mitochondrial permeability transition (MPT) and cell death.

Reactive Oxygen Species (ROS) Production: Mitochondria are the primary source of ROS due to the incomplete reduction of oxygen molecules during electron transport in the ETC. Under normal conditions, low levels of ROS act as signaling molecules. However, excessive ROS generation due to mitochondrial dysfunction can cause oxidative stress, which damages cellular components such as lipids, proteins, and mitochondrial DNA (mtDNA), contributing to the pathogenesis of cardiovascular diseases.

Apoptosis and Cell Death: Mitochondria are central regulators of apoptosis. The release of pro-apoptotic factors such as cytochrome c from the mitochondrial intermembrane space into the cytoplasm triggers caspase activation, leading to programmed cell death. Mitochondrial dysfunction in cardiovascular tissues can lead to inappropriate cell death, contributing to the progression of CVDs.

Molecular Mechanisms of Mitochondrial Dysfunction in Cardiovascular Disease

Mitochondrial dysfunction in cardiovascular disease can result from several factors, including oxidative damage, altered mitochondrial dynamics, mutations in mitochondrial DNA, and defects in mitochondrial signaling. Below are the primary molecular mechanisms contributing to mitochondrial dysfunction in cardiovascular pathologies:

1. Oxidative Stress and ROS Accumulation

Excessive ROS generation is a hallmark of mitochondrial dysfunction and a major contributor to cardiovascular disease progression. Under normal conditions, the ETC produces ROS as a byproduct of electron transfer; however, under pathological conditions such as ischemia, hypoxia, or heart failure, there is an increase in mitochondrial ROS production. This increase is due to the altered electron flow through the ETC, particularly at complex I and III, which results in the incomplete reduction of oxygen.

The accumulation of ROS causes oxidative damage to mitochondrial lipids, proteins, and mtDNA. For instance, lipid peroxidation of mitochondrial membranes leads to membrane destabilization and disruption of mitochondrial function. ROS also modify proteins involved in mitochondrial dynamics and bioenergetics, impairing the capacity of mitochondria to generate ATP. Furthermore, oxidative damage to mtDNA leads to mutations that compromise the mitochondrial respiratory chain complexes, creating a vicious cycle of mitochondrial dysfunction.

2. Mitochondrial Permeability Transition (MPT) and Calcium Overload

Mitochondrial permeability transition is a critical event in mitochondrial dysfunction. The opening of the mitochondrial permeability transition pore (mPTP) occurs when the inner mitochondrial membrane becomes permeable to ions and small molecules, disrupting the electrochemical gradient required for ATP production. Under pathological conditions such as ischemia-reperfusion injury, excessive ROS and calcium overload activate the mPTP, leading to mitochondrial swelling, loss of membrane potential, and the release of pro-apoptotic factors (e.g., cytochrome c), triggering cell death.

Calcium overload plays a significant role in mitochondrial dysfunction. During stress conditions like ischemia, excessive intracellular calcium is taken up by mitochondria, causing mitochondrial matrix expansion and rupture of the mitochondrial membrane. This exacerbates cellular injury and promotes cell death pathways in the myocardium, contributing to myocardial infarction and heart failure.

3. Mitochondrial Dynamics Dysregulation

Mitochondrial dynamics refer to the continuous processes of mitochondrial fusion and fission that maintain mitochondrial quality and function. In response to cellular stress, mitochondria can undergo fission to segregate damaged components or fusion to promote functional compensation. Mitochondrial fission is regulated by dynamin-related protein 1 (DRP1), while fusion is mediated by mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1). In cardiovascular diseases, this dynamic balance is often disrupted, leading to mitochondrial fragmentation, reduced mitochondrial function, and increased susceptibility to apoptosis.

In heart failure, for example, the upregulation of DRP1 and downregulation of fusion proteins contribute to mitochondrial fragmentation, reduced ATP production, and elevated ROS levels. This dysfunction is exacerbated by altered signaling pathways, including those associated with autophagy (mitophagy), which is responsible for removing damaged mitochondria. Dysfunctional mitophagy further impairs mitochondrial quality control, worsening cardiac injury.

4. Mitochondrial DNA Mutations

Mitochondrial DNA is more prone to mutations than nuclear DNA due to its proximity to the ETC and lack of protective histones. In cardiovascular diseases, mutations in mtDNA contribute to defective mitochondrial function. For example, mutations in genes encoding subunits of the OXPHOS complexes (such as ATP6, ND1, or CYTB) lead to impaired ATP synthesis and defective mitochondrial bioenergetics, contributing to myocardial ischemia and heart failure.

Mitochondrial mutations may also affect the regulation of ROS production and the activation of apoptotic pathways, accelerating tissue damage and organ dysfunction.

Therapeutic Approaches Targeting Mitochondrial Dysfunction in Cardiovascular Disease

Given the critical role of mitochondria in cardiovascular disease, several therapeutic strategies have been developed to target mitochondrial dysfunction and restore normal mitochondrial function. These include:

1. Mitochondrial Antioxidants

Mitochondrial-targeted antioxidants, such as MitoQ, MitoTEMPO, and SkQ1, have been developed to specifically target ROS within mitochondria. These compounds aim to reduce oxidative stress, limit mitochondrial damage, and improve mitochondrial function. Clinical studies are ongoing to assess the efficacy of these antioxidants in reducing myocardial injury and improving outcomes in heart failure and ischemic heart disease.

2. Mitochondrial Biogenesis Activation

Stimulating mitochondrial biogenesis to increase the number of functional mitochondria is another potential therapeutic strategy. Activators of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis, are being investigated as potential treatments for heart failure. Exercise training is a natural way to activate PGC-1α and increase mitochondrial function, which has been shown to improve cardiac outcomes in patients with heart failure.

3. MPTP Inhibition

Inhibitors of the mPTP, such as cyclosporine A, have been studied for their potential to prevent ischemia-reperfusion injury by inhibiting pore opening. By preserving mitochondrial integrity, these inhibitors may help reduce myocardial damage and improve survival after myocardial infarction.

4. Gene Therapy and Mitochondrial Transplantation

Gene therapy approaches, including the use of CRISPR/Cas9 to correct mitochondrial DNA mutations, hold promise in treating mitochondrial diseases. Additionally, mitochondrial transplantation, where healthy mitochondria are delivered to damaged cardiac cells, is an emerging area of research, with the potential to restore mitochondrial function and improve heart function in patients with severe myocardial injury.

Conclusion

Mitochondrial dysfunction plays a central role in the pathogenesis of cardiovascular diseases, contributing to impaired ATP production, increased ROS production, and cell death. Understanding the molecular mechanisms underlying mitochondrial dysfunction provides critical insights into the development of novel therapeutic strategies. Approaches targeting mitochondrial biogenesis, oxidative stress, mitochondrial dynamics, and mPTP inhibition offer promising avenues for the treatment of cardiovascular diseases and could lead to more effective management of conditions such as heart failure, ischemic heart disease, and hypertension. However, further research and clinical trials are needed to fully elucidate the potential of these therapeutic strategies in improving cardiovascular health.

[cheyannemallas]

Strategies for Enhancing Mitochondrial Function: A Comprehensive Review by Cheyanne Mallas

Mitochondria are essential organelles that play a fundamental role in cellular energy production and overall metabolic health says Cheyanne Mallas. Dysfunction of these powerhouses has been linked to various diseases and aging processes. Therefore, understanding and enhancing mitochondrial function have emerged as critical areas of scientific research. This review aims to provide an authoritative overview of strategies and interventions that have shown promise in enhancing mitochondrial function says Cheyanne Mallas.

1. Exercise:

Regular physical activity has been consistently shown to enhance mitochondrial function. Both aerobic and resistance exercises have been associated with increased mitochondrial biogenesis, improved respiratory capacity, and enhanced mitochondrial antioxidant defenses. The mechanisms underlying these effects include activation of key signaling pathways, such as the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway, which regulates mitochondrial biogenesis and oxidative metabolism.

2. Caloric restriction:

Caloric restriction, without malnutrition, has been shown to extend lifespan and improve mitochondrial function. Reduced caloric intake activates cellular stress response pathways, such as the sirtuin family of proteins, which promote mitochondrial biogenesis and improve mitochondrial efficiency. Intermittent fasting and time-restricted feeding are alternative dietary approaches that have also demonstrated similar effects on mitochondrial health.

3. Nutritional interventions:

Certain dietary components and supplements have been found to positively influence mitochondrial function. These include polyphenols, such as resveratrol and curcumin, which activate mitochondrial biogenesis and enhance mitochondrial antioxidant defenses. Furthermore, micronutrients like coenzyme Q10, alpha-lipoic acid, and carnitine play essential roles in mitochondrial energy production and can be supplemented to support mitochondrial function.

4. Pharmacological interventions:

Several pharmacological agents have shown potential in enhancing mitochondrial function. For instance, compounds targeting the mitochondrial electron transport chain, such as idebenone and MitoQ, have displayed beneficial effects on mitochondrial respiration and oxidative stress. Other drugs, such as metformin, rapamycin, and nicotinamide riboside, have been shown to activate mitochondrial pathways and improve mitochondrial function in various experimental models.

5. Environmental factors:

Certain environmental factors can impact mitochondrial function. Chronic exposure to environmental toxins, including heavy metals and pollutants, can impair mitochondrial respiration and increase oxidative stress. Conversely, exposure to mild stressors like heat or cold can induce cellular adaptations, including improved mitochondrial function, through hormetic mechanisms.

6. Mitochondrial-targeted therapies:

Emerging research focuses on developing targeted therapies that directly improve mitochondrial function. These include mitochondrial-targeted antioxidants, mitochondrial uncouplers, and selective modulators of mitochondrial metabolism. However, further research is needed to fully understand their efficacy and safety profiles says Cheyanne Mallas.

In conclusion, enhancing mitochondrial function is a multifaceted endeavor that requires a comprehensive approach. Regular exercise, caloric restriction, specific dietary interventions, pharmacological agents, and environmental modifications all hold promise for improving mitochondrial function. Integrating these strategies into clinical practice may offer potential therapeutic avenues for various diseases associated with mitochondrial dysfunction. However, further research is needed to fully elucidate the optimal combination and dosage of interventions for specific conditions.

[healthtimetaylor]

Strawberry methanolic extract promotes browning in 3T3-L1 cells.

PMID:  Food Funct. 2020 Jan 9. Epub 2020 Jan 9. PMID: 31915782 Abstract Title:  Strawberry (Fragaria× ananassa cv. Romina) methanolic extract promotes browning in 3T3-L1 cells. Abstract:  In recent years, the conversion of white adipocytes to brown-like adipocytes by pharmacological and dietary compounds has gained attention as an effective strategy to fight obesity. Strawberry bioactive compounds present several biological activities including antioxidant, anti-inflammatory, anti-cancer, anti-atherosclerotic and antiadipogenic properties. However, to the best of our knowledge, the possible role of strawberry bioactive compounds in white adipose tissue (WAT) browning has never been explored. Our results demonstrated that a strawberry methanolic extract (SE) significantly reduced 3T3-L1 pre-adipocytes differentiation, and down-regulated the mRNA expression of the adipogenic transcription factors CCAAT/enhancer-binding protein (C/REB-α) and peroxisome proliferation-activated receptor (PPAR-γ). It also down-regulated the mRNA expression of resistin and angiotensinogen, two genes considered as markers of white adipocytes, while increased the mRNA expression of pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) and uncoupling protein 1 (UCP1) which, conversely, are brown adipocyte-specific markers. Likewise, SE stimulated AMP-activated protein kinase (AMPKα), sirtuin 1 (Sirt1) and the peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), suggesting a possible increase in mitochondrial biogenesis. It also stimulated oxygen consumption rate and uncoupled respiration. Taken together, all these results suggest that SE induces brown fat-like phenotype in 3T3-L1 cells and may have potential therapeutic implications for treatment and/or prevention of obesity.

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[rejuvinationstayyoung]

Rejuvenate Cells by Growing New Mitochondria Mitochondrial dysfunction is a primary cause of age-related decline.1-7 In a revealing study, a team of researchers showed that muscle tissue of a 90-year-old man contained 95% damaged mitochondria compared to almost no damage in that of a 5-year-old.8 When one looks at the boundless energy of a child compared to an elderly person, the devastating impact of mitochondrial degradation become instantly apparent. A myriad of recent scientific reports link defective and deficient mitochondria to virtually all degenerative diseases including Alzheimer’s, type 2 diabetes, heart failure, and cancer.9-13 Up until now, the best we could do was protect and improve the function of existing mitochondria using nutrients like L-carnitine, lipoic acid, and coenzyme Q10. In an unprecedented breakthrough, a compound has been discovered that promotes the growth of new mitochondria structures within aging cells!14 In this article, you will discover how this novel compound can help reverse cellular aging by activating genes that stimulate mitochondrial biogenesis, which means the generation of new mitochondria. The more functional mitochondria you have in your cells, the greater your overall health and durability. Mitochondria are the only cell components (other than the nucleus) to possess their own DNA. This means mitochondria have the ability to replicate and increase their number within a single human cell. Human cells may house anywhere from 2 to 2,500 mitochondria,15-17 depending on tissue type, antioxidant status, and other factors. A growing number of biologists espouse the theory that mitochondrial number and function determine human longevity.18-20 To put it simply, the more functional mitochondria you have in your cells, the greater your overall health and durability. The problem is that as we age, our mitochondria degrade and become dysfunctional. Age-related destruction of the mitochondria occurs more rapidly than in other cell components, meaning that for most people it is loss of functional mitochondria that ultimately leads to personal extinction. The challenge aging humans face is that methods to increase the generation of new mitochondria are difficult to adhere to. Up until recently, the only natural ways to stimulate mitochondrial biogenesis were calorie restriction or exhaustive physical activity. A natural agent with the power to safely induce mitochondrial biogenesis would mark an extraordinary advance in the quest to halt and reverse cellular aging. A compound called pyrroloquinoline quinone or PQQ is rapidly emerging as that nutrient. PQQ: A Quantum Leap That May Reverse Cellular Aging PQQ (pyrroloquinoline quinone) plays a critical role across a range of basic life functions. As an ultra potent antioxidant, it provides extraordinary defense against mitochondrial decay: PQQ’s chemical structure enables it to withstand exposure to oxidation up to 5,000 times greater than vitamin C.21 When combined with CoQ10, research shows just 20 mg per day of PQQ can significantly preserve and enhance memory, attention, and cognition in aging humans.22 But the most exciting revelation on PQQ emerged early in 2010, when researchers found it not only protected mitochondria from oxidative damage—it also stimulated growth of new mitochondria!14 PQQ Is an Essential Micronutrient PQQ is ubiquitous in the natural world. It has been found in all plant species tested and is present in human milk. Humans, however, are not capable of synthesizing it.23 This has led researchers to classify PQQ as an essential micronutrient. PQQ’s potential to stimulate mitochondrial biogenesis was foreshadowed by early findings indicating its central role in growth and development across multiple forms of life. PQQ has been shown to be a potent growth factor in plants, bacteria, and higher organisms.21,24,25 Pre-clinical studies reveal that when deprived of dietary PQQ, animals exhibit stunted growth, compromised immunity, impaired reproductive capability, and most importantly, fewer mitochondria in their tissue. Rates of conception, the number of offspring, and survival rates in juvenile animals are also significantly reduced in the absence of PQQ.26-28 When PQQ is introduced back into the diet, it reverses these effects, restoring systemic function while simultaneously increasing mitochondrial number and energy efficiency. These compelling data prompted a team of researchers at the University of California-Davis to specifically analyze PQQ’s influence on cell signaling pathways involved in the formation of new mitochondria.14 Their work, published last year, led to several extraordinary discoveries. They found that PQQ’s critical biological roles stem from its ability to activate genes directly involved in cellular energy metabolism, development, and function.14 Their findings shed light on results from favorable prior studies. For example, PQQ deficiency in juvenile mice results in a 20-30% reduction in the number of mitochondria in the liver, elevated blood glucose, and impairment in oxygen metabolism.26 These are hallmark indicators of mitochondrial dysfunction. Yet when PQQ was put back into the diet, these pathological effects were reversed, along with an increase observed of new mitochondria. This and additional animal model data28 taken together confirm PQQ’s ability to significantly boost mitochondrial number and function—a key to cellular anti-aging and longevity. The sidebar on the below reveals the complex mechanisms by which PQQ activates genes that stimulate mitochondrial biogenesis. Protecting Against Mitochondria-generated Free Radicals As the primary energy engines of our cells, the mitochondria rank among the structures most vulnerable to destruction from oxidative damage. The formidable free radical-scavenging capacity of PQQ furnishes the mitochondria considerable antioxidant protection. At the core of this capacity is an extraordinary molecular stability.35 As a bioactive coenzyme, PQQ actively participates in the energy transfer within the mitochondria that supplies the body with most of its bioenergy (like CoQ10). Unlike other antioxidant compounds, the stability of PQQ allows it to carry out thousands of electron transfers without undergoing molecular breakdown. It has been proven especially effective in neutralizing the ubiquitous superoxide and hydroxyl radicals.36 According to the most recent research, “PQQ is 30 to 5,000 times more efficient in sustaining redox cycling . . . than other common [antioxidant compounds], e.g. ascorbic acid.”37 Protection Against Brain Aging PQQ has been shown to optimize function of the entire central nervous system. It reverses cognitive impairment caused by chronic oxidative stress in pre-clinical models, improving performance on memory tests.40 It has also been shown to safeguard a gene involved in the development of Parkinson’s disease (called DJ-1) from self-oxidation—an early step in the onset of Parkinson’s.41 Reactive nitrogen species (RNS), like reactive oxygen species, impose severe stresses on damaged neurons.42 They arise spontaneously following stroke and spinal cord injuries and have been shown to account for a substantial proportion of subsequent long-term neurological damage. PQQ directly suppresses RNS in experimentally induced strokes.43 It also provides additional protection by blocking gene expression of inducible nitric oxide synthase, a major source of RNS, following spinal cord injury.44 PQQ protects brain cells against damage following ischemia-reperfusion injury—the inflammation and oxidative damage that result from the sudden return of blood and nutrients tissues deprived of them by stroke.45 Given immediately before induction of stroke in animal models, PQQ significantly reduces the size of the damaged brain area.46 This finding implies that if a person were to suffer a temporary loss of cerebral blood flow due to cardiac arrest, stroke, or trauma, that having PQQ in their body would afford considerable protection against permanent brain damage. PQQ also beneficially interacts with brain neurotransmitter systems. In particular, PQQ protects neurons by modifying the important NMDA receptor site.47,48 NMDA is a powerful mediator of “excitotoxicity,” a response to long-term overstimulation of neurons that is associated with many neurodegenerative diseases and seizures.49-51 PQQ protects against neurotoxicity induced by other toxins, including mercury.52,53 A mounting body of evidence points to PQQ as a potent intervention in Alzheimer’s and Parkinson’s disease. Both are triggered by accumulation of abnormal proteins that initiate a cascade of oxidative events resulting in brain cell death. How PQQ Generates New Mitochondria Mitochondrial biogenesis can be defined as the growth and division of pre-existing mitochondria. This phenomenon is not only accompanied by increased mitochondria numbers, but also their size and mass. Mitochondrial biogenesis requires the coordinated synthesis and import of 1,000-1,500 proteins where they facilitate the production of healthy new mitochondria. Mitochondrial biogenesis occurs through the combined effects of genes activated by PQQ via the following three mechanisms: PQQ increases expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha or PGC-1α. PGC-1α is a “master regulator” gene that mobilizes your cells’ response to various external triggers. It directly activates genes that boost mitochondrial and cellular respiration, growth, and reproduction. Its capacity to modulate cellular metabolism at the genetic level favorably affects blood pressure, cholesterol and triglyceride breakdown, and the onset of obesity.29 PQQ activates a signaling protein known as cAMP-response element-binding protein or CREB. The CREB gene plays a pivotal role in embryonic development and growth. It also beneficially interacts with histones, molecular compounds shown to protect and repair cellular DNA. CREB also stimulates the growth of new mitochondria.30 PQQ regulates a recently discovered gene called DJ-1. As with PGC-1α and CREB, DJ-1 is intrinsically involved in cell function and survival. It has been shown to prevent cell death by combating intensive antioxidant stress and is of particular importance to brain health and function. DJ-1 damage and mutation have been conclusively linked to the onset of Parkinson’s disease and other neurological disorders.31-34 PQQ prevents development of alpha-synuclein, the protein responsible for Parkinson’s disease.54 It also protects nerve cells from the oxidizing ravages of the Alzheimer’s-causing amyloid-beta protein.55 A 2010 study revealed that PQQ could prevent formation of amyloid-beta molecular structures.56 These effects were traced to three distinct biochemical mechanisms described in the sidebar above. PQQ has also been shown to protect memory and cognition in aging animals and humans.22,57 It stimulates production and release of nerve growth factor in cells that support neurons in the brain.58 This may partially explain why PQQ supplementation of aging rats resulted in marked retention of their maximum memory function.57 In humans, supplementation with 20 mg per day of PQQ resulted in improvements on tests of higher cognitive function in a group of middle-aged and elderly people.22 These effects were significantly amplified when the subjects also took 300 mg per day of CoQ10. Presumably a lower dose of the more absorbable ubiquinol form of CoQ10 would provide the same benefit as 300 mg of ubiquinone. PQQ has also been shown to protect memory and cognition in both aging animals and humans. Cardiovascular Defense As with strokes, damage in heart attacks is inflicted via ischemia-reperfusion injury. Ischemia-reperfusion means loss of blood flow (ischemia) to part of the body and the subsequent re-flow (reperfusion) when blood flow is restored. Cells are injured when blood flow is interrupted and often sustain even greater damage when blood flow is suddenly restored. Supplementation with PQQ reduces the size of ischemia-reperfusion damaged areas in animal models of acute myocardial infarction (heart attack).59 This occurs whether the supplement is given before or after the ischemic event itself. To further investigate this potential, researchers at the VA Medical Center at UC-San Francisco compared PQQ with metoprolol, a commonly prescribed beta blocker that is standard post-heart attack clinical treatment.60 Given alone, both treatments reduced the damaged areas’ size and protected against heart muscle dysfunction. When they were given together, the left ventricle’s pumping pressure was enhanced. The combination also increased mitochondrial energy-producing functions—but the effect was small compared with the better response seen with PQQ alone!60 And only PQQ favorably reduced lipid peroxidation. The remarkable conclusion: “PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.”60 Subsequent research from the same team has demonstrated that PQQ helps heart muscle cells resist acute oxidative stress.61 The mechanism? Preserving and enhancing mitochondrial function. Why Mitochondria Are So Vulnerable to Free Radical Damage The death spiral of our mitochondria is accelerated by the very physiological function they must perform, i.e. energy production. As the cell’s power generators, mitochondria are the site of enormous and constant oxidative activity that spews out toxic free radicals. To make matters worse, relative to nuclear DNA, mitochondrial DNA possesses few defenses against free radical damage.38,39 DNA in the cell’s nucleus is protected by numerous “guardian” proteins that blunt the impact of free radicals. No such repair systems exist to protect mitochondrial DNA. Nuclear DNA also enjoys superior structural defenses. It is housed within a protective double-membrane that separates it from the rest of the cell. This double-membrane is complemented by a dense matrix of filament proteins called the nuclear lamina, a kind of hard shell casing to further buffer DNA from external impacts. By comparison, mitochondrial DNA is left almost entirely exposed: it attaches directly to the inner membrane where the mitochondria’s electrochemical furnace rages continuously, generating an enormous volume of toxic reactive oxygen species. This is why supplementation with lipoic acid, carnosine, and other mitochondrial-protecting antioxidants is so important. The extraordinary antioxidant capacity of PQQ represents a powerful new intervention that may effectively reinforce the mitochondria’s meager defenses. Summary Cellular aging is intimately associated with the decline in mitochondrial number and functionality. Nutrients that provide protection to existing mitochondria include resveratrol, carnosine, lipoic acid, L-carnitine, and CoQ10. During the course of normal aging, however, the number of functional mitochondria pathologically diminishes, leading to a host of debilitating disorders followed by death of the organism. For the first time in scientific history, a natural compound called PQQ is available to increase the functionality of existing mitochondria while promoting the generation of new mitochondria inside aging cells. If you have questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027. References 1. Bliznakov EG. Aging, mitochondria, and coenzyme Q(10): the neglected relationship. Biochimie. 1999 Dec;81(12):1131-2. 2. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989 Mar 25;1(8639):642-5. 3. Lanza IR, Nair KS. Mitochondrial metabolic function assessed in vivo and in vitro. Curr Opin Clin Nutr Metab Care. 2010 Jul 7. 4. Mota MP, Peixoto FM, Soares JF, et al. Influence of aerobic fitness on age-related lymphocyte DNA damage in humans: relationship with mitochondria respiratory chain and hydrogen peroxide production. Age (Dordr). 2010 Mar 20. 5. Tranah G. Mitochondrial-nuclear epistasis: Implications for human aging and longevity. Ageing Res Rev. 2010 Jun 25. 6. Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010 Jun 25. 7. Wei YH, Ma YS, Lee HC, Lee CF, Lu CY. Mitochondrial theory of aging matures—roles of mtDNA mutation and oxidative stress in human aging. Zhonghua Yi Xue Za Zhi (Taipei). 2001 May;64(5):259-70. 8. Linnane AW, Kovalenko S, Gingold EB. The universality of bioenergetic disease: age-associated cellular bioenergetic degradation and amelioration therapy. Ann N Y Acad Sci. 1998 Nov 20;854:202-13. 9. Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res. 2010 Jul 16. 10. Conley KE, Amara CE, Jubrias SA, Marcinek DJ. Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Exp Physiol. 2007 Mar;92(2):333-9. 11. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001 Jun;33(6):1065-89. 12. Maruszak A, Zekanowski C. Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Jul 15. 13. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 2006 May;1067:182-90. 14. Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1 alpha expression. J Biol Chem. 2010 Jan 1;285:142-52. 15. Bruce A, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. New York, NY: Garland Publishing, Inc.;1994. 16. Voet D, Voet JG, Pratt CW. Fundamentals of Biochemistry: Life at the Molecular Level. 2nd ed. New Jersey: John Wiley and Sons, Inc.; 2006:547. 17. Pike RL, Brown M. Nutrition: An Integrated Approach. New York, NY: Prentice-Hall; 1984:450-84. 18. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89. 19. Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion, and life span. Curr Aging Sci. 2009 Mar;2(1):12-27. 20. Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci. 2004;107:355-364. 21. Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77. 22. Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style. 2009;21:13(7):50-3. 23. Smidt CR, Bean-Knudsen D, Kirsch DG, Rucker RB. Does the intestinal microflora synthesize pyrroloquinoline quinone? Biofactors.1991 Jan;3(1):53-9. 24. Stites TE, Mitchell AE, Rucker RB. Physiological importance of quinoenzymes and the O-quinone family of cofactors. J Nutr. 2000 Apr;130(4):719-27. 25. Choi O, Kim J, Kim JG, et al. Pyrroloquinoline quinone is a plant growth promotion factor produced by Pseudomonas fluorescens B16. Plant Physiol. 2008 Feb;146(2):657-68. 26. Stites T, Storms D, Bauerly K, et al. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr. 2006 Feb;136(2):390-6. 27. Steinberg F, Stites TE, Anderson P, et al. Pyrroloquinoline quinone improves growth and reproductive performance in mice fed chemically defined diets. Exp Biol Med (Maywood). 2003 Feb;228(2):160-6. 28. Bauerly KA, Storms DH, Harris CB, et al. Pyrroloquinoline quinone nutritional status alters lysine metabolism and modulates mitochondrial DNA content in the mouse and rat. Biochim Biophys Acta. 2006 Nov;1760(11):1741-8. 29. Entrez Gene: PPARGC1A peroxisome proliferator-activated receptor gamma, coactivator 1 alpha [ Homo sapiens ] GeneID: 10891. 30. Entrez Gene: CREBBP CREB binding protein [ Homo sapiens ] GeneID: 1387. 31. Zhong N, Xu J. Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. Hum Mol Genet. 2008 Nov 1;17(21):3357-67. 32. Mitsumoto A, Nakagawa Y. DJ-1 is an indicator for endogenous reactive oxygen species elicited by endotoxin. Free Rad Res. 2001; 35(6):885-93. 33. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H. Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. Biol Pharm Bull. 2008 Jul;31(7):1321-6. 34. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004 Feb;5(2):213-8. 35. Paz MA, Martin P, Fluckiger R, Mah J, Gallop PM. The catalysis of redox cycling by pyrroloquinoline quinone (PQQ), PQQ derivatives, and isomers and the specificity of inhibitors. Anal Biochem. 1996;238:145-9. 36. Urakami T, Yoshida C, Akaike T, Maeda H, Nishigori H, Niki E. Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo. J Nutr Sci Vitaminol (Tokyo). 1997 Feb;43(1):19-33. 37. Stites TE, Mitchell AE, Rucker RB. Physiological importance of quinoenzymes and the O-quinone family of cofactors. J Nutr. 2000 Apr;130(4):719-27. 38. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol. 1995;27:647-53. 39. Miquel J. An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutat Res. 1992 Sep;275(3-6):209-16. 40. Ohwada K, Takeda H, Yamazaki M, et al. Pyrroloquinoline quinone (PQQ) prevents cognitive deficit caused by oxidative stress in rats. J Clin Biochem Nutr. 2008 Jan;42:29-34. 41. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H. Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. Biol Pharm Bull. 2008 Jul;31(7):1321-6. 42. Ono K, Suzuki H, Sawada M. Delayed neural damage is induced by iNOS-expressing microglia in a brain injury model. Neurosci Lett. 2010 Apr 5;473(2):146-50. 43. Zhang Y, Rosenberg PA. The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation. Eur J Neurosci. 2002 Sep;16(6):1015-24. 44. Hirakawa A, Shimizu K, Fukumitsu H, Furukawa S. Pyrroloquinoline quinone attenuates iNOS gene expression in the injured spinal cord. Biochem Biophys Res Commun. 2009 Jan 9;378(2):308-12. 45. Jensen FE, Gardner GJ, Williams AP, Gallop PM, Aizenman E, Rosenberg PA. The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury. Neuroscience. 1994 Sep;62(2):399-406. 46. Zhang Y, Feustel PJ, Kimelberg HK. Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Res. 2006 Jun 13;1094(1):200-6. 47. Aizenman E, Hartnett KA, Zhong C, Gallop PM, Rosenberg PA. Interaction of the putative essential nutrient pyrroloquinoline quinone with the N-methyl-D-aspartate receptor redox modulatory site. J Neurosci. 1992 Jun;12(6):2362-9. 48. Aizenman E, Jensen FE, Gallop PM, Rosenberg PA, Tang LH. Further evidence that pyrroloquinoline quinone interacts with the N-methyl-D-aspartate receptor redox site in rat cortical neurons in vitro. Neurosci Lett. 1994 Feb 28;168(1-2):189-92. 49. Hossain MA. Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain. Epilepsy Behav. 2005 Sep;7(2):204-13. 50. Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009 Apr;30(4):379-87. 51. Foran E, Trotti D. Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxid Redox Signal. 2009 Jul;11(7):1587-602. 52. Hara H, Hiramatsu H, Adachi T. Pyrroloquinoline quinone is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity. Neurochem Res. 2007 Mar;32(3):489-95. 53. Zhang P, Xu Y, Sun J, Li X, Wang L, Jin L. Protection of pyrroloquinoline quinone against methylmercury-induced neurotoxicity via reducing oxidative stress. Free Radic Res. 2009 Mar;43(3):224-33. 54. Kobayashi M, Kim J, Kobayashi N, et al. Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein. Biochem Biophys Res Commun. 2006 Oct 27;349(3):1139-44. 55. Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett. 2009 Oct 30;464(3):165-9. 56. Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion. 2010 Jan;4(1):26-31. 57. Takatsu H, Owada K, Abe K, Nakano M, Urano S. Effect of vitamin E on learning and memory deficit in aged rats. J Nutr Sci Vitaminol (Tokyo). 2009;55(5):389-93. 58. Murase K, Hattori A, Kohno M, Hayashi K. Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes. Biochem Mol Biol Int. 1993 Jul;30(4):615-21. 59. Zhu BQ, Zhou HZ, Teerlink JR, Karliner JS. Pyrroloquinoline quinone (PQQ) decreases myocardial infarct size and improves cardiac function in rat models of ischemia and ischemia/reperfusion. Cardiovasc Drugs Ther. 2004 Nov;18(6):421-31. 60. Zhu BQ, Simonis U, Cecchini G, et al. Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther. 2006 Jun;11(2):119-28. 61. Tao R, Karliner JS, Simonis U, et al. Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes. Biochem Biophys Res Commun. 2007 Nov 16;363(2):257-62.

[cancersfakianakis1]

Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in non-small cell lung cancer (NSCLC) patients. We found a strong correlation between CD68 TAM immunostaining and positron emission tomography (PET) 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of NSCLC patients. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 NSCLC patients from the TCGA database. TAM secreted tumor necrosis factor-α (TNF-α) to promote tumor cell glycolysis while increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies including immunotherapy. http://bit.ly/2R6yzrE

[itsmedicinesfakianakis]

SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice

Background. Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. Methods and Results. Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM). Conclusions. Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM. from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2fBfzjj

from OtoRhinoLaryngology - Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2fC5zWX

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Reclaim Vitality: The Science Behind Mitochondrial Biogenesis

Mitochondrial biogenesis is the cellular process of increasing the number of mitochondria, the organelles responsible for generating energy. This process is essential for maintaining cellular health and vitality, particularly in tissues with high energy demands, such as muscles. Mitochondrial biogenesis is often triggered by increased energy demand, usually resulting from exercise, caloric restriction, or the intake of specific nutrients.

Mitochondria are the energy producers of the cell, generating ATP, the energy currency of the cell, through oxidative phosphorylation. As cells face greater energy demands, they need more mitochondria to meet these requirements efficiently. The increase in mitochondrial numbers allows cells to produce more energy and better adapt to stress, thus enhancing overall health, recovery, and performance.

Key Factors Involved in Mitochondrial Biogenesis

Several molecular regulators drive mitochondrial biogenesis, with the most important being:

PGC-1α ActivationPGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is recognized as the master regulator of mitochondrial biogenesis. This protein plays a pivotal role in controlling the transcription of nuclear genes that encode mitochondrial proteins. When activated by external stimuli like exercise, PGC-1α interacts with transcription factors like NRF-1 and NRF-2 to drive the production of new mitochondria. This results in increased mitochondrial DNA (mtDNA) replication and the synthesis of mitochondrial proteins necessary for energy production and cellular respiration.

AMPK & SirtuinsAMPK (AMP-activated protein kinase) is another critical regulator that responds to low energy levels within the cell (a high AMP ratio). It activates PGC-1α, which, in turn, increases the number of mitochondria. AMPK is activated during energy-demanding activities such as endurance exercise and fasting. Sirtuins (SIRT1) are a class of NAD+-dependent enzymes that also regulate mitochondrial biogenesis. Sirtuins, especially SIRT1, deacetylate PGC-1α, further activating it to promote the transcription of mitochondrial genes. Both AMPK and sirtuins respond to energy deprivation, whether through physical exertion or caloric restriction, helping cells increase energy efficiency and prolong cellular longevity.

Antioxidant Defense and Cellular ResilienceOne of the benefits of mitochondrial biogenesis is the enhancement of cellular resilience through improved antioxidant defences. Mitochondria are not only energy producers but also sources of reactive oxygen species (ROS), which can damage cells if not adequately managed. By increasing the number of healthy mitochondria, cells improve their ability to manage oxidative stress. New mitochondria are typically more efficient at energy production and less likely to produce excess ROS, reducing overall cellular damage. This process helps to protect cells from age-related decline and stress-induced damage.

How Mitochondrial Biogenesis Impacts Health and Performance

Mitochondrial biogenesis is essential for maintaining optimal energy production, particularly during periods of increased physical activity or stress. In muscle cells, the increased number of mitochondria leads to improved ATP generation, enhancing endurance and reducing fatigue during prolonged exercise. This is particularly important for athletes or individuals who engage in regular physical activity, as their muscles require a constant supply of energy for performance and recovery.

For general health, mitochondrial biogenesis supports metabolic efficiency and longevity. In metabolic disorders like type 2 diabetes and obesity, mitochondrial dysfunction often results in impaired energy metabolism and increased oxidative stress. By promoting mitochondrial biogenesis, cells can restore normal mitochondrial function, improving insulin sensitivity and energy balance. Furthermore, mitochondrial biogenesis may help reduce the risk of chronic diseases related to ageing by maintaining cellular energy production and reducing oxidative stress.

Beyond exercise and metabolic health, mitochondrial biogenesis is also a key factor in the body’s ability to adapt to various stressors, whether environmental or nutritional. The increase in mitochondrial capacity allows cells to better handle changes in energy demand, supporting recovery and cellular adaptation. For instance, during periods of caloric restriction, mitochondrial biogenesis helps the body use energy more efficiently, contributing to longer-term health benefits, including improved longevity and resistance to age-related diseases.

Supporting Mitochondrial Biogenesis with Nutraceuticals

In addition to lifestyle factors like exercise and caloric restriction, certain nutraceuticals can support mitochondrial biogenesis. Mitokatlyst™-E is one such product that targets mitochondrial function, optimising energy production, and promoting muscle recovery. By stimulating the molecular pathways involved in mitochondrial biogenesis, such products can enhance the body’s ability to adapt to stress, recover more efficiently, and improve overall cellular function.

Conclusion

Mitochondrial biogenesis is a vital process that supports energy production, cellular health, and adaptability to environmental and physical stressors. By regulating pathways such as PGC-1α, AMPK, and sirtuins, cells can increase mitochondrial content to meet higher energy demands, promote muscle recovery, and improve overall vitality. Products like Mitokatlyst™-E are designed to optimise mitochondrial function, helping the body adapt to stress and maintain optimal cellular health. By supporting mitochondrial biogenesis, we can improve energy efficiency, enhance physical performance, and promote long-term health and resilience.

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Salugenesis in Mitochondria: Enhancing Cellular Health and Energy Production

The field of salugenesis—focused on promoting natural healing and optimizing health—finds a particularly vital area of application in mitochondrial function. Mitochondria, known as the powerhouses of the cell, generate the energy required for cellular processes through oxidative phosphorylation. As such, they are fundamental to cellular health and play a critical role in the body’s capacity to repair, maintain balance, and regenerate. Salugenesis in mitochondria involves optimizing mitochondrial function, enhancing bioenergetics, and addressing cellular aging and disease, with the ultimate aim of boosting cellular resilience and overall health.

Mitochondria’s Role in Salugenesis: The Cellular Powerhouse and Beyond

Mitochondria are essential not only for energy production but also for regulating metabolic homeostasis, immune response, and apoptosis (programmed cell death). Given their central role, mitochondria are a key target in salugenesis, with a focus on:

ATP Production and Energy: Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), which fuels cellular functions. Salugenic approaches aim to support and enhance ATP production to increase cellular energy levels.

ROS and Oxidative Stress: Mitochondria produce reactive oxygen species (ROS) as byproducts of energy production. While ROS are part of normal cell signaling, excessive levels can lead to oxidative damage. Salugenesis aims to manage ROS production, supporting mitochondrial health without triggering oxidative damage.

Mitochondrial Biogenesis: This is the process by which new mitochondria are formed. Encouraging mitochondrial biogenesis is a key aspect of salugenesis, as more mitochondria enhance cellular energy output and resilience to stress.

Apoptosis and Cellular Repair: Mitochondria regulate apoptosis, a process critical to removing damaged or dysfunctional cells. By supporting efficient cellular turnover, salugenesis in mitochondria contributes to overall tissue health.

Mechanisms of Salugenesis in Mitochondria

Salugenesis in mitochondria can be achieved by targeting several key cellular and molecular mechanisms:

Mitochondrial Biogenesis Pathways: Stimulating mitochondrial biogenesis through pathways like PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) helps increase mitochondrial numbers. Salugenesis promotes biogenesis through interventions such as exercise, caloric restriction, and compounds like resveratrol and NAD+ boosters.

Mitophagy and Autophagy: Mitophagy is the process by which damaged mitochondria are selectively degraded, allowing the cell to maintain a healthy pool of mitochondria. Autophagy can be activated by fasting, certain types of exercise, and compounds that stimulate cellular cleanup. Salugenic approaches aim to enhance mitophagy, thus preventing the buildup of dysfunctional mitochondria.

Support of Mitochondrial Membrane Potential: The inner mitochondrial membrane’s electrochemical gradient, essential for ATP production, is maintained through optimal function of electron transport chain (ETC) complexes. Salugenesis supports membrane integrity with nutrient-rich diets, antioxidant supplements, and healthy lifestyle habits to maintain efficient ATP synthesis.

Nutritional Support for Mitochondria: Certain nutrients and cofactors are integral to mitochondrial function. Coenzyme Q10 (CoQ10), L-carnitine, alpha-lipoic acid, and B vitamins are essential for energy production. Salugenesis recommends incorporating these nutrients through diet or supplementation to maintain optimal mitochondrial health.

Hormesis and Controlled Stressors: Mild stressors, like heat, cold exposure, and intermittent fasting, activate mitochondrial biogenesis and increase resilience. These hormetic stressors are central to salugenesis, as they encourage mitochondria to adapt, thereby enhancing cellular health and longevity.

Practical Applications: Salugenic Interventions for Mitochondrial Health

Exercise: Physical activity, particularly endurance and resistance training, stimulates mitochondrial biogenesis and enhances ATP production. Exercise-induced PGC-1α activation supports energy production and cellular repair.

Dietary Interventions: Diets rich in antioxidants (such as vitamins C and E), polyphenols (e.g., resveratrol), and omega-3 fatty acids help protect mitochondria from oxidative damage. Caloric restriction and intermittent fasting have also been shown to stimulate mitochondrial biogenesis.

Supplementation: NAD+ boosters (like nicotinamide riboside), CoQ10, alpha-lipoic acid, and L-carnitine directly support mitochondrial energy metabolism and reduce oxidative stress.

Red and Near-Infrared Light Therapy: Photobiomodulation, using red or near-infrared light, penetrates cells to stimulate mitochondrial ATP production and improve cellular function, aiding in tissue repair and energy production.

Hormetic Stress Therapies: Cold therapy (cryotherapy) and sauna therapy activate stress-response pathways in mitochondria, encouraging adaptations that improve cellular health and resilience.

Mitochondrial Dysfunction and Implications for Health

Mitochondrial dysfunction is associated with numerous age-related and chronic diseases, including neurodegenerative conditions (e.g., Parkinson’s and Alzheimer’s), cardiovascular disease, and metabolic disorders. Dysfunctional mitochondria lead to reduced ATP production, increased ROS production, and compromised cellular integrity. Salugenic interventions target mitochondrial health to address or prevent these conditions by supporting mitochondrial efficiency and reducing cellular stress.

Salugenesis in Mitochondrial Research and Future Directions

Research in salugenesis and mitochondria continues to advance, with a focus on uncovering precise mechanisms by which mitochondrial function can be optimised. Future directions include:

Mitochondrial Medicine: Developing therapies specifically targeting mitochondrial pathways, such as pharmacological agents that mimic the effects of caloric restriction, NAD+ supplementation, and mitochondrial transplantation.

Gene Therapy: Exploring genetic interventions to enhance mitochondrial function, targeting nuclear and mitochondrial genes associated with energy production, ROS management, and mitophagy.

Precision Mitochondrial Care: Personalized approaches using genetic and metabolic profiling to determine the most effective interventions for optimizing mitochondrial health on an individual basis.

Anti-Aging Research: Extending mitochondrial health could play a significant role in anti-aging, slowing cellular senescence, and enhancing tissue repair.

Conclusion

Salugenesis in mitochondria offers an innovative approach to health by focusing on cellular energy, repair, and resilience. By supporting mitochondrial biogenesis, enhancing antioxidant defenses, and promoting optimal mitochondrial dynamics, salugenesis paves the way for improved health, longevity, and disease resistance. As research continues to shed light on the dynamic relationship between mitochondria and overall health, salugenic practices may become essential components in preventive medicine and longevity science.

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The Role of Mitochondria in Menopause

Introduction

Menopause signifies a pivotal transition in a woman's life, characterized by the cessation of ovarian function and a marked decline in estrogen levels. This phase is associated with various physiological changes and an increased risk of several health conditions, including metabolic syndrome, osteoporosis, and cardiovascular diseases. Recent studies have illuminated the significant role of mitochondria—the organelles often referred to as the "powerhouses of the cell"—in the physiological processes that accompany menopause. This article seeks to elucidate the multifaceted roles of mitochondria in menopause, highlighting their involvement in energy metabolism, hormonal regulation, oxidative stress management, and overall cellular health.

Mitochondrial Structure and Function

Mitochondria are double-membraned organelles that possess their own circular DNA (mtDNA), a remnant of their evolutionary origin from ancestral prokaryotic cells. These organelles are essential for several critical functions, including:

Adenosine Triphosphate (ATP) Production: Mitochondria generate ATP via oxidative phosphorylation (OXPHOS), facilitated by the electron transport chain (ETC) embedded in the inner mitochondrial membrane.

Metabolic Pathways: Mitochondria are central to various metabolic pathways, including the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and the urea cycle, integrating cellular energy production and metabolism.

Regulation of Apoptosis: Mitochondria play a crucial role in apoptosis by releasing pro-apoptotic factors such as cytochrome c, thereby initiating programmed cell death essential for cellular homeostasis.

Mitochondrial Dysfunction in Menopause

The decline in estrogen during menopause is closely linked to changes in mitochondrial function:

Mitochondrial Biogenesis: Estrogen is known to stimulate mitochondrial biogenesis through the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The reduction in estrogen levels during menopause leads to diminished PGC-1α activity, resulting in decreased mitochondrial density and compromised function.

Oxidative Stress: Mitochondrial respiration generates reactive oxygen species (ROS) as byproducts. In the context of menopause, reduced estrogen levels can impair the body's antioxidant defenses, leading to an increase in oxidative stress. Elevated ROS can cause damage to mitochondrial DNA, proteins, and lipids, resulting in further mitochondrial dysfunction.

Altered Energy Metabolism: The menopausal transition is frequently associated with metabolic syndrome, characterized by increased fat accumulation and insulin resistance. Mitochondrial dysfunction is a contributing factor to impaired fatty acid oxidation and energy dysregulation, resulting in increased visceral fat deposition.

Hormonal Regulation and Mitochondrial Function

Mitochondria are integral to the synthesis of steroid hormones, including estrogen. While the ovaries serve as the primary site for estrogen production, peripheral tissues, such as adipose tissue, can synthesize estrogen from androgens via the aromatization process. Adequate mitochondrial function is crucial for this synthesis. Consequently, mitochondrial dysfunction may exacerbate symptoms associated with estrogen deficiency.

Moreover, mitochondrial involvement in cortisol metabolism may also be significant. Cortisol, produced by the adrenal glands, influences energy metabolism and stress response. Dysregulation in cortisol metabolism due to mitochondrial dysfunction can lead to increased fatigue and mood disturbances commonly observed during menopause.

Inflammation and Mitochondrial Dysfunction

Mitochondrial dysfunction is closely linked to chronic inflammation, frequently observed in menopausal women. As mitochondrial function declines, the production of pro-inflammatory cytokines increases, contributing to systemic inflammation. This chronic inflammatory state may exacerbate various menopausal symptoms, including joint pain, mood disorders, and cardiovascular risks.

Mitochondria also play a role in inflammasome activation, a multi-protein complex critical to the immune response. Dysregulation of this pathway in the context of mitochondrial dysfunction can lead to excessive inflammation, further complicating health during menopause.

Interventions to Support Mitochondrial Health

Given the integral role of mitochondria in menopause, various interventions may be employed to support mitochondrial function:

Physical Activity: Regular exercise has been shown to enhance mitochondrial biogenesis and improve oxidative phosphorylation. Exercise stimulates the expression of PGC-1α, promoting mitochondrial health and improving metabolic outcomes.

Nutritional Interventions: Diets rich in antioxidants (e.g., vitamins C and E, polyphenols) can help mitigate oxidative stress. Omega-3 fatty acids, found in fish oil, support mitochondrial function by reducing inflammation.

Caloric Restriction and Intermittent Fasting: These practices enhance mitochondrial efficiency and promote autophagy, a process that eliminates damaged mitochondria and supports cellular health.

Supplementation: Certain supplements, such as Coenzyme Q10, alpha-lipoic acid, and L-carnitine, may directly support mitochondrial function and reduce oxidative stress.

Hormone Replacement Therapy (HRT): For some women, HRT may alleviate menopausal symptoms and support mitochondrial function by restoring estrogen levels; however, this approach requires careful consideration of individual risks and benefits.

Conclusion

Mitochondria are critical contributors to the physiological changes associated with menopause, influencing energy metabolism, hormonal balance, oxidative stress, and inflammation. A comprehensive understanding of the intricate relationship between mitochondrial function and menopausal symptoms can inform targeted interventions to support women's health during this transition. By prioritizing mitochondrial health through lifestyle modifications and potential therapeutic strategies, women may enhance their quality of life and mitigate health risks associated with menopause. Continued research is essential to explore the complex interplay between mitochondrial dynamics and menopausal physiology, paving the way for novel therapeutic approaches and interventions.

[healthtimetaylor]

Black ginseng and ginsenoside Rb1 act as potential functional anti-obesity food agents.

PMID:  Nutrients. 2019 Nov 12 ;11(11). Epub 2019 Nov 12. PMID: 31726767 Abstract Title:  Black Ginseng and Ginsenoside Rb1 Promote Browning by Inducing UCP1 Expression in 3T3-L1 and Primary White Adipocytes. Abstract:  In this study, we investigated the effects of black ginseng (BG) and ginsenoside Rb1, which induced browning effects in 3T3-L1 and primary white adipocytes (PWATs) isolated from C57BL/6 mice. BG and Rb1 suppressed the expressions of CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding transcription factor-1c (SREBP-1c), whereas the expression level of peroxisome proliferator-activated receptor gamma (PPARγ) was increased. Furthermore, BG and Rb1 enhanced the protein expressions of the brown-adipocyte-specific markers PR domain containing16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and uncoupling protein 1 (UCP1). These results were further supported by immunofluorescence images of mitochondrial biogenesis. In addition, BG and Rb1 induced expressions of brown-adipocyte-specific markerproteins by AMP-activated protein kinase (AMPK) activation. BG and Rb1 exert antiobesity effects by inducing browning in 3T3-L1 cells and PWATs through AMPK-mediated pathway activation. We suggest that BG and Rb1 act as potential functional antiobesity food agents.

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[healthtimetaylor]

Resveratrol could be useful in counteracting seizure-induced neuronal damage.

PMID:  Int J Mol Sci. 2019 Feb 25 ;20(4). Epub 2019 Feb 25. PMID: 30823590 Abstract Title:  Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway. Abstract:  Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke,and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1αexpression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damagein the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.

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[healthtimetaylor]

Cyanidin-3-glucoside enhances mitochondrial function and biogenesis in a human hepatocyte cell line.

PMID:  Cytotechnology. 2018 Dec ;70(6):1519-1528. Epub 2018 Aug 28. PMID: 30155610 Abstract Title:  Cyanidin-3-glucoside enhances mitochondrial function and biogenesis in a human hepatocyte cell line. Abstract:  Mitochondrial dysfunction has been identified as one of the primary factors contributing to liver diseases. Pathways that control mitochondrial biogenesis are potential therapeutic targets for the amelioration of hepatocyte dysfunction and liver disease. Research on natural pharmacological agents that ameliorate liver diseases has intensified over the last two decades. Cyanidin-3-glucoside (Cy3g), a dietary flavonoid compound extracted from a wide variety of fruits and vegetables, reportedly has several beneficial health effects. In this study, we used an adult human hepatoma cell line (HuH7) to investigate the effects of the Cy3g polyphenolic compound on mitochondrial function and biogenesis in vitro. An increase in intracellular mitochondrial reductase levels was observed after treatment with Cy3g, but cytotoxicity was not induced. In addition, mitochondrial membrane potential and ATP production were increased following Cy3g treatment. Cy3g treatment also resulted in a dose- and time-dependent upregulation of the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcription factor considered a master regulator of mitochondrial biogenesis and metabolism. Additionally, the expression of sirtuin 1 (SIRT1), which plays a key role in deacetylating PGC-1α, was also increased in a dose- and time-dependent manner. Cy3g treatment also increased the expression of downstream PGC-1α genes, nuclear respiratory factor 1 and mitochondrial transcription factor A (TFAM). Our results suggest that Cy3g has potential as a hepatoprotective therapeutic agent that enhances mitochondrial function and biogenesis in hepatocytes.

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[healthtimetaylor]

Resveratrol protects against post-contrast acute kidney injury in rabbits with diabetic nephropathy.

PMID:  Front Pharmacol. 2019 ;10:833. Epub 2019 Jul 26. PMID: 31402864 Abstract Title:  Resveratrol Protects Against Post-Contrast Acute Kidney Injury in Rabbits With Diabetic Nephropathy. Abstract:  Resveratrol (Res) is a multi-functional polyphenol compound that has protective functions in acute kidney diseases. Here, we examined whether the resveratrol could ameliorate post-contrast acute kidney injury (PC-AKI) following diabetic nephropathy (DN), and explored any underlying mechanism(s)and. Twenty-four rabbits with DN were randomly divided into four groups: control (Cont), resveratrol (Res), iohexol (PC-AKI), and resveratrol plus iohexol (Res+PC-AKI) groups. Functional magnetic resonance imaging, renal histology, blood and urinary biomarkers, silent information regulator l (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), hypoxia-inducible transcription factor-1α (HIF-1α), and apoptosis-associated protein expression were assessed. Forexperiments, renal tubular epithelial (HK-2) cells subjected to high glucose conditions were treated with resveratrol, Ex527, an SIRT1 inhibitor, or 2-methoxyestradiol (2-MeOE2), HIF-1α inhibitor, before treatment with iohexol. With regard to the rabbit model of acute renal injury in DN, compared to the PC-AKI group, the Res+PC-AKI group showed decreased levels of cystatin C and urinary neutrophil gelatinase-associated lipocalin, increased pure molecular diffusion () and the fraction of water flowing in capillaries (), a decreased apparent relaxation rate (), renal injury score and apoptosis rate, increased protein expression levels of SIRT1 and PGC-1α, and decreased levels of HIF-1α and apoptosis-associated protein. In addition, iohexol decreased HK-2 cell survival and increased the cell apoptosis rate; results were reversed after treating cells with resveratrol. Resveratrol reduced renal hypoxia, mitochondrial dysfunction and renal tubular cell apoptosis by activating SIRT1-PGC-1α-HIF-1α signaling pathways in PC-AKI with DN.

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These results suggest that β-caryophyllene ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.

PMID:  Biomolecules. 2019 Jul 31 ;9(8). Epub 2019 Jul 31. PMID: 31370242 Abstract Title:  β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR-γ Receptors. Abstract:  β-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that tempers inflammation. An interaction between the CB2 receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) has been suggested and PPAR-γ activation exerts anti-arthritic effects. The aim of this study was to characterize the therapeutic activity of BCP and to investigate PPAR-γ involvement in a collagen antibody induced arthritis (CAIA) experimental model. CAIA was induced through intraperitoneal injection of a monoclonal antibody cocktail and lipopolysaccharide (LPS; 50 μg/100 μL/ip). CAIA animals werethen randomized to orally receive either BCP (10 mg/kg/100 μL) or its vehicle (100 μL of corn oil). BCP significantly hampered the severity of the disease, reduced relevant pro-inflammatory cytokines, and increased the anti-inflammatory cytokine IL-13. BCP also decreased joint expression of matrix metalloproteinases 3 and 9. Arthritic joints showed increased COX2 and NF-ĸB mRNA expression and reduced expression of the PPARγ coactivator-1 alpha, PGC-1α, and PPAR-γ. These conditions were reverted following BCP treatment. Finally, BCP reduced NF-ĸB activation and increased PGC-1α and PPAR-γ expression in human articular chondrocytes stimulated with LPS. These effects were reverted by AM630, a CB2 receptor antagonist. These results suggest that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ.

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