New Discovery Shows Mitochondria Direct Human Health and the Best Supplements to Help Them

For decades, mitochondria were relegated to the status of cellular "powerhouses" in biology textbooks—organelles whose primary function was simply producing ATP through oxidative phosphorylation. However, groundbreaking discoveries over the past two decades have fundamentally transformed our understanding of these ancient endosymbionts. Far from being mere energy factories, mitochondria have emerged as sophisticated signaling hubs that orchestrate cellular fate, communicate bidirectionally with the nucleus, and serve as master regulators of metabolism, aging, and disease susceptibility. This paradigm shift began crystallizing with the revolutionary discovery of MOTS-c, the first mitochondrial-encoded peptide shown to regulate nuclear gene expression, challenging the long-held assumption that genetic information flow was unidirectional from nucleus to mitochondria (Lee et al., 2015).

Contemporary research reveals mitochondria as dynamic centers of integration for fundamental cellular processes including growth, development, survival, and programmed cell death. These organelles possess intricate quality control mechanisms, including the mitochondrial unfolded protein response (UPRmt) and coordinated stress responses that communicate cellular metabolic status to the nucleus (Quirós et al., 2016). Furthermore, direct physical contact sites between mitochondrial and nuclear membranes facilitate metabolite and protein transfer, while the delicate balance between mitochondrial biogenesis and mitophagy determines cellular fate and organismal healthspan (Eisner et al., 2018). Understanding these mechanisms has profound implications not only for basic biology but also for therapeutic interventions targeting age-related diseases, metabolic disorders, and neurodegeneration.

MOTS-c: Revolutionary Discovery of Mitochondrial-Nuclear Communication

The discovery of MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) represented a watershed moment in mitochondrial biology.

Lee and colleagues (2015) identified this 16-amino acid peptide encoded within the mitochondrial 12S rRNA gene, demonstrating for the first time that mitochondria could produce regulatory peptides capable of translocating to the nucleus and directly influencing nuclear gene expression. This finding shattered the traditional view of genetic information flow and established mitochondria as active participants in transcriptional regulation rather than passive recipients of nuclear commands.

MOTS-c exhibits remarkable metabolic regulatory properties, particularly in response to cellular stress and nutrient availability. Under conditions of glucose restriction or metabolic stress, MOTS-c translocates from the cytoplasm to the nucleus where it binds to DNA and regulates the expression of nuclear-encoded genes involved in metabolism, stress response, and antioxidant defense (Lee et al., 2015). This retrograde signaling mechanism allows mitochondria to communicate their functional status directly to the nucleus, coordinating cellular responses to metabolic challenges. Research has demonstrated that MOTS-c treatment improves insulin sensitivity, prevents diet-induced obesity, and extends healthspan in mouse models, positioning it as a potential therapeutic target for metabolic diseases (Lee et al., 2015; Reynolds et al., 2021).

The evolutionary implications of MOTS-c discovery are profound. Its existence suggests that the mitochondrial genome, though drastically reduced from its bacterial ancestor, retains cryptic coding capacity beyond the canonical 13 protein-coding genes. This has prompted researchers to reevaluate the mitochondrial genome for other hidden open reading frames, leading to the identification of additional mitochondrial-derived peptides (MDPs) with diverse biological functions (Kim et al., 2017). These peptides appear to function as mitochondrial stress signals, communicating organellar dysfunction to cellular and systemic regulatory networks—a concept that has fundamentally altered our understanding of mitochondrial-nuclear crosstalk and metabolic homeostasis.

Mitochondria as Integration Centers for Cellular Processes

Beyond energy production, mitochondria serve as critical integration hubs coordinating cellular growth, development, survival, and death decisions. This integrative function stems from their unique position at the nexus of multiple signaling pathways and their sensitivity to cellular nutrient status, redox state, and stress signals (Chandel, 2014). Mitochondria continuously assess cellular energy demands and nutrient availability, translating this information into appropriate metabolic, proliferative, or survival responses.

During cellular growth and proliferation, mitochondria undergo extensive remodeling to meet increased bioenergetic and biosynthetic demands. They provide not only ATP but also essential metabolic intermediates required for macromolecular synthesis, including citrate for lipid biosynthesis, aspartate for nucleotide production, and one-carbon units for methylation reactions (Martínez-Reyes & Chandel, 2020). Mitochondrial metabolism directly influences epigenetic modifications through the production of metabolites such as acetyl-CoA, α-ketoglutarate, and S-adenosylmethionine, which serve as substrates or cofactors for chromatin-modifying enzymes. This metabolic-epigenetic axis allows mitochondria to influence gene expression programs that determine cell fate and differentiation trajectories (Martínez-Reyes & Chandel, 2020).

Mitochondria also function as central regulators of programmed cell death pathways. The intrinsic apoptotic pathway is initiated at the mitochondrial outer membrane through the BAX/BAK-mediated permeabilization, releasing cytochrome c and other pro-apoptotic factors into the cytosol (Tait & Green, 2013). Beyond classical apoptosis, mitochondria participate in various other cell death modalities including necroptosis, ferroptosis, and pyroptosis, each characterized by distinct mitochondrial dysfunction patterns. The decision between cell survival and death depends on the integration of multiple mitochondrial signals including calcium homeostasis, reactive oxygen species (ROS) production, membrane potential, and metabolite availability—positioning mitochondria as ultimate arbiters of cellular fate (Tait & Green, 2013).

The Mitochondrial Unfolded Protein Response and Stress Coordination

The mitochondrial unfolded protein response (UPRmt) represents an elegant adaptive mechanism through which mitochondria communicate proteotoxic stress to the nucleus, initiating transcriptional programs that restore mitochondrial proteostasis.

When misfolded or unfolded proteins accumulate within mitochondria—due to genetic mutations, oxidative damage, or imbalanced nuclear-mitochondrial gene expression—the UPRmt activates nuclear transcription factors that upregulate mitochondrial chaperones, proteases, and antioxidant defenses (Quirós et al., 2016).

In mammals, the UPRmt involves activation of the transcription factors ATF4, ATF5, and CHOP, which coordinate the expression of mitochondrial quality control genes. The signaling mechanism involves the accumulation of unimported mitochondrial precursor proteins in the cytosol, triggering the integrated stress response through eIF2α phosphorylation (Fiorese et al., 2016). This response is remarkably specific, distinguishing mitochondrial proteotoxic stress from endoplasmic reticulum stress or cytosolic protein misfolding, demonstrating sophisticated subcellular stress compartmentalization.

Activation of the UPRmt extends beyond simple protein quality control, influencing longevity, metabolic homeostasis, and disease resistance. Research in C. elegans demonstrated that mild mitochondrial stress early in life activates the UPRmt, leading to extended lifespan through a phenomenon termed "mitohormesis" (Durieux et al., 2011).

This concept suggests that low-level mitochondrial stress triggers adaptive responses that enhance cellular resilience and stress resistance—a principle with potential therapeutic implications. The UPRmt also coordinates with other cellular stress responses, including the integrated stress response, autophagy, and innate immunity, creating a comprehensive cellular defense network centered on mitochondrial function (Quirós et al., 2016).

Dysregulation of the UPRmt has been implicated in various age-related diseases, including neurodegeneration, metabolic syndrome, and cancer. In neurodegenerative conditions such as Alzheimer's and Parkinson's disease, impaired UPRmt activation may contribute to the accumulation of dysfunctional mitochondria and progressive neuronal loss (Fiorese et al., 2016).

Conversely, cancer cells often exploit the UPRmt to survive metabolic stress and therapeutic interventions, suggesting that modulating this pathway could offer novel therapeutic opportunities. Understanding the molecular mechanisms governing UPRmt activation and its integration with other stress responses remains an active area of investigation with significant translational potential.

Mitochondrial-Nuclear Contact Sites and Molecular Transfer

Recent advances in super-resolution microscopy and molecular biology have revealed direct physical contact sites between mitochondria and the nucleus, challenging the traditional view of these organelles as spatially and functionally segregated compartments. These mitochondria-associated nuclear envelope membranes facilitate direct metabolite exchange, calcium signaling, and protein transfer between mitochondria and the nuclear compartment (Desai et al., 2020).

The physical tethering of mitochondria to the nuclear envelope is mediated by protein complexes that span both organellar membranes. These contact sites are enriched in metabolic enzymes and transport proteins that facilitate the efficient transfer of key metabolites including ATP, acetyl-CoA, and NAD+, molecules that directly influence nuclear processes such as transcription, DNA repair, and epigenetic modifications (Desai et al., 2020). The proximity of mitochondria to the nucleus ensures rapid communication of metabolic status and allows coordinated responses to cellular energy demands.

Calcium signaling represents another critical function of mitochondrial-nuclear contact sites. Calcium microdomains form at these junctions, allowing mitochondria to buffer nuclear calcium transients and influence calcium-dependent transcription factors such as NFAT and CREB (Lynes et al., 2016). This calcium crosstalk is particularly important in excitable cells such as neurons and cardiomyocytes, where coordinated nuclear-mitochondrial calcium signaling regulates gene expression programs in response to electrical activity and metabolic demand.

Furthermore, these contact sites may facilitate the transfer of proteins and nucleic acids between compartments. Recent evidence suggests that certain nuclear-encoded mitochondrial proteins may be partially assembled at the nuclear envelope before import into mitochondria, while mitochondrial-derived peptides like MOTS-c may utilize these contact sites for nuclear entry (Desai et al., 2020). The discovery of mitochondrial DNA in the nucleus and cytosol, particularly during stress or aging, suggests that these contact sites may also regulate the release of mitochondrial danger signals that activate innate immune responses. Understanding the molecular architecture and regulatory mechanisms governing mitochondrial-nuclear contact sites represents a frontier in cell biology with implications for understanding metabolic disease, aging, and cellular stress responses.

Mitochondrial Biogenesis and Mitophagy: Balancing Quality and Quantity

Mitochondrial homeostasis requires a delicate balance between the generation of new mitochondria (biogenesis) and the selective removal of damaged organelles (mitophagy). This dynamic equilibrium determines mitochondrial quality, cellular bioenergetic capacity, and ultimately influences cell fate decisions ranging from proliferation to senescence and death (Palikaras et al., 2015).

Mitochondrial biogenesis is orchestrated primarily through the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator 1-alpha), which coordinates the expression of nuclear-encoded mitochondrial genes with mitochondrial DNA replication and transcription. PGC-1α activity is regulated by multiple signaling pathways responsive to energy status, including AMPK, sirtuins, and mTOR, allowing cells to adjust mitochondrial mass according to metabolic demands (Scarpulla, 2011). Exercise, caloric restriction, and cold exposure all stimulate mitochondrial biogenesis through PGC-1α activation, enhancing oxidative capacity and metabolic flexibility.

Conversely, mitophagy—the selective autophagy of mitochondria—removes dysfunctional organelles that might otherwise accumulate and cause cellular damage through excessive ROS production, pro-apoptotic signaling, or metabolic dysfunction. The PINK1/Parkin pathway represents the best-characterized mitophagy mechanism, wherein damaged mitochondria with reduced membrane potential accumulate PINK1 kinase on their outer membrane, recruiting the E3 ubiquitin ligase Parkin, which ubiquitinates outer membrane proteins and targets the organelle for autophagosomal degradation (Pickles et al., 2018). Genetic mutations in PINK1 or Parkin cause familial Parkinson's disease, highlighting the critical importance of mitophagy in neuronal health and demonstrating how impaired mitochondrial quality control contributes to neurodegeneration.

The coordination between biogenesis and mitophagy determines net mitochondrial function and cellular fate. Enhanced mitophagy without compensatory biogenesis leads to mitochondrial depletion, bioenergetic crisis, and cell death, while impaired mitophagy with ongoing biogenesis results in the accumulation of dysfunctional mitochondria, cellular senescence, and tissue aging (Palikaras et al., 2015). Aging is characterized by declining mitophagy efficiency and dysregulated biogenesis, contributing to the accumulation of damaged mitochondria observed in aged tissues. Interventions that enhance mitophagy or stimulate biogenesis, including exercise, dietary restriction, and pharmacological activators, show promise for extending healthspan and preventing age-related diseases (Palikaras et al., 2015).

Research-Backed Mitochondrial Supplements: Translating Science to Therapy

The explosion of knowledge regarding mitochondrial biology has spurred interest in nutritional and pharmacological interventions that support mitochondrial function. Several compounds have emerged with substantial research support demonstrating beneficial effects on mitochondrial health, bioenergetics, and healthspan.

Coenzyme Q10: The Electron Transport Chain Essential

Coenzyme Q10 (CoQ10), also known as ubiquinone, serves as an essential mobile electron carrier in the mitochondrial electron transport chain, shuttling electrons from Complexes I and II to Complex III while also functioning as a lipid-soluble antioxidant (Hernández-Camacho et al., 2018). CoQ10 levels decline with aging and are reduced in various pathological conditions including heart failure, neurodegenerative diseases, and statin-induced myopathy. Supplementation with CoQ10 has demonstrated benefits in multiple clinical contexts, particularly cardiovascular disease, where it improves endothelial function, reduces oxidative stress, and may improve outcomes in heart failure patients (Hernández-Camacho et al., 2018).

The bioavailability of CoQ10 varies substantially depending on formulation, with ubiquinol (the reduced form) demonstrating superior absorption compared to ubiquinone. Clinical trials have shown that CoQ10 supplementation can improve mitochondrial ATP production, reduce oxidative damage, and enhance exercise capacity in individuals with mitochondrial dysfunction (Hernández-Camacho et al., 2018). In neurological conditions, CoQ10 has shown promise in Parkinson's disease and migraine prophylaxis, though results have been mixed across studies. The established safety profile and biological plausibility of CoQ10 make it one of the most widely recommended mitochondrial support supplements, particularly for individuals taking statins or experiencing age-related mitochondrial decline.

Pyrroloquinoline Quinone: Biogenesis Promoter and Neuroprotectant

Pyrroloquinoline quinone (PQQ) is a redox cofactor found in plant foods that has garnered attention for its ability to stimulate mitochondrial biogenesis and provide neuroprotection. Unlike CoQ10, which participates directly in electron transport, PQQ functions as a signaling molecule that activates pathways promoting new mitochondria formation (Chowanadisai et al., 2010). Studies have demonstrated that PQQ activates PGC-1α and related transcription factors, leading to increased mitochondrial number and enhanced cellular energetics.

In animal models, PQQ supplementation has shown remarkable neuroprotective effects, protecting neurons from oxidative stress, excitotoxicity, and ischemic damage (Zhang et al., 2009). These neuroprotective properties appear to stem from multiple mechanisms including direct antioxidant activity, stimulation of nerve growth factor production, and enhancement of mitochondrial function. Human clinical trials, though limited, have demonstrated that PQQ supplementation improves cognitive function and reduces markers of inflammation, particularly when combined with CoQ10 (Nakano et al., 2016).

The mitochondrial biogenesis-promoting effects of PQQ position it as a potential intervention for conditions characterized by mitochondrial insufficiency, including age-related cognitive decline, metabolic syndrome, and neurodegenerative diseases. However, the optimal dosing, bioavailability, and long-term effects of PQQ supplementation require further investigation. Current evidence suggests doses of 10-20 mg daily are well-tolerated and produce measurable improvements in mitochondrial function and cognitive performance (Chowanadisai et al., 2010).

Alpha-Lipoic Acid: Mitochondrial Antioxidant and Metabolic Enhancer

Alpha-lipoic acid (ALA) is a naturally occurring compound that functions as a cofactor for mitochondrial enzymes involved in energy metabolism, particularly the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. Beyond its role as an enzymatic cofactor, ALA serves as a potent antioxidant capable of regenerating other antioxidants including vitamins C and E, glutathione, and CoQ10 (Rochette et al., 2013). Its amphipathic nature allows it to function in both aqueous and lipid environments, providing comprehensive cellular antioxidant protection.

Clinical research has demonstrated that ALA supplementation improves glucose metabolism and insulin sensitivity in individuals with type 2 diabetes and metabolic syndrome (Rochette et al., 2013). These effects appear to result from enhanced mitochondrial glucose oxidation, reduced oxidative stress, and improved insulin signaling. ALA has also shown efficacy in treating diabetic neuropathy, with multiple studies demonstrating improvements in neuropathic symptoms following intravenous or oral supplementation (Ziegler et al., 2004).

Particularly relevant to aging research, ALA has been shown to reverse age-related mitochondrial dysfunction in animal models. Studies by Hagen and colleagues demonstrated that old rats supplemented with ALA showed improved mitochondrial function, reduced oxidative damage, and enhanced metabolic activity compared to unsupplemented controls (Hagen et al., 2002). These findings suggest that ALA may address fundamental aging mechanisms related to mitochondrial decay. The combination of ALA with acetyl-L-carnitine has shown synergistic effects on mitochondrial function and cognitive performance in aged animals, though human trials replicating these dramatic effects remain limited (Hagen et al., 2002).

Turmeric's Positive Mitochondrial Effects:

1. Diabetes Research (2014) A study using diabetic db/db mice found that curcumin treatment restored mitochondrial functions to normal levels in both liver and kidney tissue. Specifically, curcumin improved oxygen consumption, increased liver mitochondrial ATPase activity, and decreased lipid peroxidation markers (TBARS) in kidney mitochondria.

2. Neurodegenerative Disease Protection Research has shown that curcumin prevents mitochondrial dysfunction and suppresses neuronal death by targeting various pathways including ROS, apoptosis pathways, and inflammatory mediators. It also increases electron transport chain complex enzymes and alters enzymatic and non-enzymatic antioxidants.

3. Enhanced Mitochondrial Function Studies have demonstrated that curcumin treatment results in elevation of mitochondrial function and cell viability. Curcumin improves mitochondrial potential and ATP production and restores mitochondrial fusion, likely by upregulating PGC-1α protein expression.

4. Oxidative Stress in Liver In hepatocytes exposed to high free fatty acids, curcumin treatment inhibited lipoapoptosis, ROS production, and ATP depletion. The mechanism appears related to improvements in mitochondrial function and biogenesis.

5. Intestinal Health (2022) A study on oxidative stress in piglets found that dietary curcumin ameliorated jejunal damage and mitochondrial dysfunction, attenuated endoplasmic reticulum stress, and alleviated mitochondrial-associated membrane disorders.

NAD+ Precursors: Cellular Energy and Longevity Activation

Nicotinamide adenine dinucleotide (NAD+) serves as an essential coenzyme in redox reactions and a substrate for enzymes including sirtuins, PARPs, and CD38 that regulate cellular metabolism, DNA repair, inflammation, and aging. NAD+ levels decline substantially with aging across multiple tissues, and this decline is implicated in age-related metabolic dysfunction, neurodegeneration, and reduced cellular resilience (Yoshino et al., 2018). Supplementation with NAD+ precursors—including nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide—can restore NAD+ levels and improve mitochondrial function.

NMN has received particular attention following research demonstrating that it improves glucose metabolism, enhances mitochondrial function, and extends healthspan in mouse models of aging and metabolic disease (Mills et al., 2016). These effects are mediated largely through activation of sirtuins, particularly SIRT1 and SIRT3, which regulate mitochondrial function, oxidative stress resistance, and metabolic homeostasis. Human clinical trials have shown that NMN supplementation is safe and effectively increases NAD+ levels in blood and muscle tissue, with evidence of improved insulin sensitivity and physical performance in some studies (Yoshino et al., 2018).

The therapeutic potential of NAD+ precursor like B3, supplementation extends beyond metabolic enhancement to include neuroprotection, improved cardiovascular function, and enhanced DNA repair capacity. Restoring NAD+ levels may represent a fundamental anti-aging intervention that addresses multiple hallmarks of aging simultaneously by maintaining mitochondrial function, supporting cellular stress responses, and preserving genome integrity (Yoshino et al., 2018). However, questions remain regarding optimal dosing strategies, long-term safety, and which patient populations derive the greatest benefit from NAD+ augmentation.

Resveratrol: Mitochondrial Biogenesis and Caloric Restriction Mimetic

Resveratrol, a polyphenolic compound found in grapes, red wine, and certain berries, has gained prominence as a potential caloric restriction mimetic that stimulates mitochondrial biogenesis and activates longevity pathways. The biological effects of resveratrol are mediated primarily through activation of sirtuins, particularly SIRT1, which deacetylates and activates PGC-1α, leading to increased mitochondrial biogenesis and oxidative capacity (Lagouge et al., 2006).

Preclinical research demonstrated that resveratrol supplementation in mice fed a high-fat diet prevented obesity, improved insulin sensitivity, increased mitochondrial number, and extended lifespan—effects strikingly similar to those observed with caloric restriction (Baur et al., 2006). These findings generated substantial excitement about resveratrol as a potential therapeutic for metabolic diseases and aging. Mechanistic studies revealed that resveratrol enhances mitochondrial function by increasing the NAD+/NADH ratio, activating AMPK, inhibiting mTOR, and reducing inflammation (Lagouge et al., 2006).

However, translating these preclinical findings to humans has proven challenging. While resveratrol supplementation has shown benefits for glucose metabolism, endothelial function, and inflammatory markers in some human studies, the effects are generally modest and variable across trials (Timmers et al., 2011). The poor bioavailability of resveratrol, with rapid metabolism and low plasma concentrations, may limit its efficacy in humans at commonly used doses. Nonetheless, resveratrol's ability to activate mitochondrial biogenesis pathways and mimic aspects of caloric restriction makes it a valuable research tool and a compound of ongoing therapeutic interest, particularly in combination with other mitochondrial-enhancing interventions (Timmers et al., 2011).

Integrating Mitochondrial Biology and Supplementation

The convergence of basic mitochondrial biology research and nutritional supplementation creates opportunities for targeted interventions supporting healthspan and treating age-related diseases. The supplements discussed—CoQ10, PQQ, alpha-lipoic acid, NAD+ precursors, and resveratrol—each target distinct but complementary aspects of mitochondrial function. CoQ10 supports electron transport and antioxidant defense, PQQ and resveratrol stimulate mitochondrial biogenesis, alpha-lipoic acid enhances metabolic efficiency and reduces oxidative stress, while NAD+ precursors maintain the cellular energetics and sirtuin activity essential for mitochondrial health.

The mechanistic insights from MOTS-c discovery, UPRmt research, and mitochondrial-nuclear communication studies suggest that supporting mitochondrial function may have far-reaching effects beyond simple energy production. By enhancing mitochondrial quality control, maintaining efficient biogenesis-mitophagy balance, and supporting retrograde signaling to the nucleus, these interventions may optimize cellular stress responses, maintain metabolic flexibility, and promote healthy aging.

However, important caveats warrant consideration. First, supplement bioavailability, dosing, and formulation significantly impact efficacy, with substantial variation across products. Second, individual responses vary based on baseline mitochondrial function, genetic polymorphisms, age, and underlying health status. Third, while preclinical evidence is often compelling, human clinical trials frequently show more modest and variable effects, highlighting the complexity of translating animal research to human therapeutics. Finally, mitochondrial supplements should be viewed as complementary to, not replacements for, lifestyle interventions—particularly exercise and dietary patterns—which remain the most robust interventions for maintaining mitochondrial health.

Conclusion

The past two decades have witnessed a revolution in our understanding of mitochondrial biology, transforming these organelles from simple powerhouses to sophisticated signaling hubs that integrate metabolism, stress responses, and gene expression. The discovery of MOTS-c and other mitochondrial-derived peptides established bidirectional mitochondrial-nuclear communication, while research into the UPRmt, mitochondrial-nuclear contact sites, and biogenesis-mitophagy coordination revealed the complexity of mitochondrial integration into cellular homeostasis.

These fundamental insights have practical implications for health optimization and disease treatment. Research-backed supplements including CoQ10, PQQ, alpha-lipoic acid, NAD+ precursors, and resveratrol offer targeted support for mitochondrial function through complementary mechanisms. While these interventions show promise, they should be understood within the broader context of mitochondrial biology and implemented alongside lifestyle factors that fundamentally shape mitochondrial health.

Future research will undoubtedly reveal additional layers of complexity in mitochondrial signaling and regulation. Emerging topics including mitochondrial-derived vesicles, mitochondrial ROS as signaling molecules, and the role of mitochondrial dynamics in cellular fate decisions promise to further expand our understanding. As this knowledge base grows, so too will opportunities for precision interventions targeting mitochondrial function to prevent disease, extend healthspan, and optimize human performance across the lifespan.

References

Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., ... & Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. *Nature, 444*(7117), 337-342.

Chandel, N. S. (2014). Mitochondria as signaling organelles. *BMC Biology, 12*(1), 34.

Chowanadisai, W., Bauerly, K. A., Tchaparian, E., Wong, A., Cortopassi, G. A., & Rucker, R. B. (2010). Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1α expression. *Journal of Biological Chemistry, 285*(1), 142-152.

Desai, R., Frazier, A. E., Durigon, R., Patel, H., Jones, A. W., Dalla Rosa, I., ... & Pulkes, T. (2020). ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. *Brain, 143*(6), 1942-1957.

Durieux, J., Wolff, S., & Dillin, A. (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. *Cell, 144*(1), 79-91.

Eisner, V., Picard, M., & Hajnóczky, G. (2018). Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. *Nature Cell Biology, 20*(7), 755-765.

Fiorese, C. J., Schulz, A. M., Lin, Y. F., Rosin, N., Pellegrino, M. W., & Haynes, C. M. (2016). The transcription factor ATF5 mediates a mammalian mitochondrial UPR. *Current Biology, 26*(15), 2037-2043.

Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., ... & Ames, B. N. (2002). Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. *Proceedings of the National Academy of Sciences, 99*(4), 1870-1875.

Hernández-Camacho, J. D., Bernier, M., López-Lluch, G., & Navas, P. (2018). Coenzyme Q10 supplementation in aging and disease. *Frontiers in Physiology, 9*, 44.

Kim, K. H., Son, J. M., Benayoun, B. A., & Lee, C. (2017). The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. *Cell Metabolism, 28*(3), 516-524.

Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., ... & Auwerx, J. (2006). Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. *Cell, 127*(6), 1109-1122.

Lee, C., Zeng, J., Drew, B. G., Sallam, T., Martin-Montalvo, A., Wan, J., ... & Cohen, P. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. *Cell Metabolism, 21*(3), 443-454.

Lynes, E. M., Bui, M., Yap, M. C., Benson, M. D., Schneider, B., Ellgaard, L., ... & Simmen, T. (2016). Palmitoylated TMX and calnexin target to the mitochondria-associated membrane. *EMBO Journal, 31*(2), 457-470.

Martínez-Reyes, I., & Chandel, N. S. (2020). Mitochondrial TCA cycle metabolites control physiology and disease. *Nature Communications, 11*(1), 102.

Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., ... & Imai, S. I. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. *Cell Metabolism, 24*(6), 795-806.

Nakano, M., Murayama, Y., Hu, L., Ikemoto, K., Uetake, T., & Sakatani, K. (2016). Effects of antioxidant supplements (BioPQQ™) on cerebral blood flow and oxygen metabolism in the prefrontal cortex. *Advances in Experimental Medicine and Biology, 923*, 215-222.

Palikaras, K., Lionaki, E., & Tavernarakis, N. (2015). Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. *Nature, 521*(7553), 525-528.

Pickles, S., Vigié, P., & Youle, R. J. (2018). Mitophagy and quality control mechanisms in mitochondrial maintenance. *Current Biology, 28*(4), R170-R185.

Quirós, P. M., Mottis, A., & Auwerx, J. (2016). Mitonuclear communication in homeostasis and stress. *Nature Reviews Molecular Cell Biology, 17*(4), 213-226.

Reynolds, J. C., Lai, R. W., Woodhead, J. S., Joly, J. H., Mitchell, C. J., Cameron-Smith, D., ... & Sinclair, D. A. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. *Nature Communications, 12*(1), 470.

Rochette, L., Ghibu, S., Muresan, A., & Vergely, C. (2013). Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. *Canadian Journal of Physiology and Pharmacology, 93*(12), 1021-1027.

Scarpulla, R. C. (2011). Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. *Biochimica et Biophysica Acta, 1813*(7), 1269-1278.

Tait, S. W., & Green, D. R. (2013). Mitochondrial regulation of cell death. *Cold Spring Harbor Perspectives in Biology, 5*(9), a008706.

Timmers, S., Konings, E., Bilet, L., Houtkooper, R. H., van de Weijer, T., Goossens, G. H., ... & Schrauwen, P. (2011). Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. *Cell Metabolism, 14*(5), 612-622.

Yoshino, J., Baur, J. A., & Imai, S. I. (2018). NAD+ intermediates: the biology and therapeutic potential of NMN and NR. *Cell Metabolism, 27*(3), 513-528.

Zhang, Q., Shen, M., Ding, M., Shen, D., & Ding, F. (2009). The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway. *Toxicology and Applied Pharmacology, 252*(1), 62-72.

Ziegler, D., Hanefeld, M., Ruhnau, K. J., Hasche, H., Lobisch, M., Schütte, K., ... & Gries, F. A. (2004). Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a meta-analysis. *Diabetic Medicine, 21*(2), 114-121.