Unleashing Cellular Vitality: Mastering Mitochondrial Health

Mitochondria are responsible for generating more than 90% of the body's energy, primarily in the form of adenosine triphosphate (ATP) [1]. When ATP breaks down, it releases essential energy crucial for maintaining life and ensuring proper functioning of organs [2]. Key energy-consuming organs include the brain, muscles, liver, kidneys, gastrointestinal tract, heart, and lungs [3,4].

Mitochondrial Function in the Cell

Mitochondria are not only involved in energy production but also have a plethora of functions including those mentioned below [5-7]:

1. Calcium Homeostasis: Mitochondria play a vital role in regulating calcium homeostasis, and any perturbation of calcium levels leads to multiple diseases [8-10]. A more detailed look into calcium homeostasis and mitochondrial dysfunction can be found here.
2. Apoptosis: It has been well established that mitochondria have a central role in regulating apoptosis [1].
3. Fatty Acid Metabolism: Fatty acid oxidation takes place in the mitochondria [11]. Fatty acid metabolism provides energy for cells during high energy demand or when glucose levels are low [11].
4. Heme Metabolism: Heme is a common and crucial metalloorganic cofactor necessary for almost all aerobic life [12]. Hemeproteins are the essential oxygen transporters with heme as a prosthetic group. Some of the critical hemeproteins include hemoglobin, myoglobin, neuroglobin, and hemocyanin. The mitochondria are the organelles where heme production is initiated and completed [12]. Heme is then transferred to apo-hemoproteins found throughout the cell or modified covalently.
5. Reactive Oxygen Species (ROS) Regulation: One of the main by-products of aerobic respiration is ROS [13]. ROS are mainly produced in the mitochondria of cells. Mitochondria play an important role in maintaining cellular homeostasis by regulating ROS levels [14]. ROS can activate multiple signal transductions and play a vital role in aging. To learn more about the mitochondrial ROS theory of aging, read here.
6. Cell Danger Response: The Cell Danger Response (CDR) is characterized as an evolutionarily conserved metabolic reaction triggered when a cell encounters severe threats that have the potential to harm or even lead to the cell's demise [15]. Mitochondria are the critical players in regulating and controlling CDR [16,17]. To learn more about the role of mitochondria in CDR, read here.

Mitochondrial Dysfunction in Diseases

These functional roles of the mitochondrion show that it is not only the powerhouse of the cell but the most important organelle of the cell. Hence, mitochondrial dysfunction causes many diseases, some of which are listed below:

1. Chronic Fatigue: Fatigue is often characterized by a lack of energy, mental or physical tiredness, decreased endurance, and the need for prolonged recovery after physical activity [18]. Rest does not seem to alleviate this persistent and debilitating condition, which remains poorly understood despite its widespread prevalence [19]. Studies have found an association between fatigue and mitochondrial dysfunction, but more in-depth studies are required to get a clear understanding [18-21].
2. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Syndrome: The energy needs of numerous organs with high energy demand, like the nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system, are incapable of generating sufficient ATP to meet their needs when mitochondrial function is altered. One of the causes of mitochondrial dysfunction is mutation in mitochondrial DNA, leading to mitochondrial disorder [2,14,22,23]. MELAS syndrome is the name for common diseases caused by mitochondrial disorders [24]. Stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature are common symptoms of multi-organ disease MELAS syndrome [24].
3. Mitochondrial Cardiomyopathy: Key factors in the development of most heart failures are mitochondrial dysfunction and oxidative stress [5,25]. Mitochondrial cardiomyopathy refers to a heart-related condition marked by irregular heart muscle structure, function, or both. This arises due to genetic defects in the mitochondrial respiratory chain, without concurrent issues like coronary artery disease, hypertension, valvular disease, or congenital heart conditions [5,25-27].
4. Neurodegenerative Disorders: Multiple neurodegenerative disorders like Alzheimer’s, Parkinson's, Huntington's, and autism are associated with mitochondrial dysfunction [28-34].
5. Asthma: Chronic asthma is linked to mitochondrial dysfunction [35,36]. When allergens are present, the absorption of Ca²⁺ through the mitochondrial calcium uniporter (MCU) triggers an overabundance of ROS generation [36,37]. This excessive ROS production leads to the demise of lung epithelial cells, contributing to the breakdown of the epithelial barrier's function [35,38]. Changes in the entry of mitochondrial Ca²⁺ and heightened levels of cytosolic Ca²⁺ could amplify airway hyperactivity, a hallmark of asthma. As a result, both the MCU and other transporters that can disrupt mitochondrial Ca²⁺ balance present promising avenues for potential asthma treatments [35,37].

10 Natural Ways to Vitalize Mitochondrial Health

It is vital to keep your mitochondria hale and hearty to have a healthy lifestyle. There are many natural ways to boost mitochondrial function, ten of which are listed below:

1. Yoga enhances the integrity of the mitochondria by modifying the expression of transcripts responsible for maintaining mitochondrial integrity [39]. This adjustment contributes to maintaining balanced free radical levels, a pivotal factor for elevating mitochondrial copy numbers. Moreover, it enhances cytochrome c oxidase (COX-II) activity, boosts nicotinamide adenine dinucleotide (NAD+) levels, optimizes markers of oxidative stress, and raises the levels of transcripts vital for preserving mitochondrial integrity [39,40]. Consequently, it diminishes the impact of disease activity on physical and mental well-being. As a result, yoga holds promise as a supplementary therapeutic approach in mitochondrial dysfunction [39-41].
2. Calorie Restriction (CR) has been shown to increase mitochondrial biogenesis by 30% in a landmark study on male mice. The study found that implementing CR for durations of either 3 or 12 months triggered the expression of endothelial nitric oxide synthase and the formation of 3',5'-cyclic guanosine monophosphate in different tissues of male mice. This was accompanied by the generation of new mitochondria, leading to escalated oxygen consumption and ATP production. The study strongly provided proof that CR is responsible for increasing mitochondrial function [42]. Other studies have also found similar results in cell lines and animal models that CR induced the proliferation of the mitochondria via a signaling pathway involving peroxisome proliferation-activated receptor coactivator 1α [43].
3. Intermittent Fasting’s (IF) role in improving mitochondrial function is known. A study found enhanced oxygen flow and ATP production through better mitochondrial respiration, demonstrated by strong respiratory control ratios in rats following IF for eight weeks with alternate day fasting (ADF) [44,45]. Another study observed reduced heart inflammation and oxidative stress, similar to younger rats following a 24-month ADF plan [44,45]. Combining ADF IF with intense intermittent exercise also improved metabolic pathways, significantly lowering malondialdehyde levels and plasma protein oxidation [45].
4. Methylene Blue’s role in regulating mitochondrial function is well-documented [7]. Research has shown that methylene blue’s unique ability to redirect electrons within the mitochondrial electron transfer chain directly, from NADH to cytochrome c, results in increased complex IV activity, thereby boosting mitochondrial function and reducing oxidative stress [46,47]. These remarkable properties aid in curbing cell damage and enhancing cellular metabolism through mitochondrial improvements. Consequently, the impressive mitochondrial response of methylene blue has paved the way for exploring its potential applications in addressing conditions linked to mitochondrial dysfunction, including age-related issues affecting various tissues like the brain and skin [46-48]. To learn more about methylene blue, read here.
5. Nicotinamide Riboside (NR) is a precursor of NAD+, and its supplementation is known to improve mitochondrial function. In a recent twin study, twenty pairs of monozygotic twins with differing body mass indexes were given increasing amounts of NR over five months. The authors found that supplementation led to enhancements in overall NAD+ metabolism, increased muscle mitochondria count, better myoblast differentiation, and improved gut microbiota balance in both twins of each pair [49]. Other studies have also found that NAD+ and NR play a vital role in improving mitochondrial function. To learn more about the functioning of niacin, read here.
6. Curcumin is the most commonly found in turmeric and has antioxidant activities [50]. Studies have shown that curcumin can boost mitochondrial fusion activity, decrease mitochondrial fission mechanisms, and elevate mitochondrial biogenesis. Treatment with curcumin has demonstrated enhanced mitochondrial function and cell viability [50]. Curcumin potentially enhances mitochondrial potential and ATP levels and might also contribute to restoring mitochondrial fusion, likely through the upregulation of PGC-1α protein expression [50].
7. Resveratrol is a polyphenolic phytoalexin in grapes, berries, peanuts, and wines [51]. It is recognized for its antioxidant, anti-inflammatory, anti-apoptotic, and anticancer properties [52]. Studies have found that resveratrol regulates mitochondrial function, redox processes, and dynamics. Additionally, resveratrol reduces mitochondrial damage caused by specific stressors [53]. For instance, it increases the presence of antioxidant enzymes within mitochondria, consequently reducing reactive species production by these structures [52,54]. Furthermore, resveratrol initiates mitochondrial growth, leading to improvements in the bioenergetic status associated with mitochondria in mammalian cells [51,52,54].
8. Exercise plays a vital role in regulating mitochondrial functions. Studies have found that 30 minutes of daily exercise reduces mitophagy and increases longevity. A systematic review found that regular aerobic exercise enhanced mitochondrial morphology, biogenesis, dynamics, oxidative, and antioxidant capacity [55]. Thus, exercise remains our best behavioral medicine for improving mitochondrial health and individual longevity [56].
9. Melatonin is a potent antioxidant that counters free radicals and ROS generated during cellular metabolism [25]. It protects mitochondria by neutralizing ROS, hindering the opening of the mitochondrial permeability transition pore, and activating uncoupling proteins [57]. Consequently, melatonin sustains the optimal membrane potential of mitochondria, ensuring their functions remain intact. Furthermore, melatonin governs the creation and movement of mitochondria. It frequently curtails the division of mitochondria while fostering their fusion. The rhythmic oscillation in mitochondrial dynamics mirrors melatonin's natural secretion cycle, observed particularly in pineal cells and likely in other cell types [58]. Recent studies also highlight melatonin's role in promoting mitophagy and enhancing mitochondrial equilibrium [58]. To learn more about melatonin, read here.
10. Vitamin C is an essential nutrient for humans due to their inability to synthesize it from glucose [59]. It holds the capacity to enhance mitochondrial functioning. Its supplementation can mitigate excessive ROS production, safeguarding mitochondria and reducing inflammation across tissues, including skeletal muscle [59,60]. Consequently, it shows promise in enhancing recovery and athletic performance. However, the impact of antioxidant supplementation on skeletal muscle adaptation to exercise remains uncertain. While it might interfere with hormesis, where stress-induced ROS signal beneficial adaptations, it could also potentially prevent prolonged elevation of ROS caused by excessive exercise stress, leading to impaired function and damage [58-60].

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Conclusion

To have a long and healthy life, protecting the functionality of the mitochondria is of utmost importance. Mitochondria are not only the powerhouses of the cell but the most important organelles in your body. Longevity studies have shown that dysfunctional mitochondria are the root cause of numerous diseases, including neurodegenerative disorders, heart failure, and chronic fatigue. One can unleash cellular vitality by implementing natural ways to improve their mitochondrial health.

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