—A Review of “Mitochondria at the Heart of Aging: Structure, Function, and Failure”

Carry a case of water, climb several flights of stairs in a row, or suddenly exercise after sitting for a long time, and the body may be left with a few lingering “aftereffects”: muscle soreness that lasts longer than it used to, occasional twitching in the calves, tightness in the lower back, or a sense the next morning that the body has not fully loosened up. Many factors can contribute to these experiences, including changes in electrolytes, posture, exercise load, and sleep. Together, however, they point to one basic reality: once the activity stops, the body’s recovery work is only beginning. During this period, mitochondria are also busy supporting energy supply, transport, clearance, and rebuilding.

After a muscle contracts, calcium ions must return to the appropriate locations and ion gradients across the cell membrane need to be restored. Proteins that have been stretched, oxidized, or misfolded must be inspected: those that remain usable are repaired and retained, while those that are too severely damaged are broken down and recycled. New building materials must then be delivered to the sites that need repair. Recovery depends on energy supply, transport, clearance, and rebuilding reconnecting into a coordinated rhythm.

On April 24, 2026, Hany E. Marei published the review “Mitochondria at the Heart of Aging: Structure, Function, and Failure” in Volume 24 of the Journal of Translational Medicine, article 716.[1] As a review, the paper primarily integrates existing research. Marei places mitochondria at the intersection of structure, energy conversion, mitochondrial DNA, quality control, inflammatory signaling, and cell fate, using this framework to address a broader question:

Why have mitochondria become central to aging research? And why does aging so often appear as a simultaneous loss of coordination reserve across multiple maintenance systems?

The first five sections of this article follow the main framework of the review and add explanations from classic mechanistic studies. The participant numbers, doses, and intervention periods involving 146 adults, 45 healthy participants, and 38 older adults come from the separately cited original human studies.

1. Start with Structure: Why Mitochondria Are More Than Cellular “Batteries”

Mitochondria can be thought of as small energy-conversion stations built inside cells. The outer membrane defines the boundary, while the inner membrane repeatedly folds inward to form structures known as cristae. These folds are like adding more workbenches within a limited factory floor, creating more surface area on which respiratory-chain complexes and ATP synthase can be organized.[1][3]

As carbohydrates, fats, and some amino acids from food are broken down, they transfer high-energy electrons to the respiratory chain. The electrons move stepwise through complexes in the inner mitochondrial membrane, and the energy released is used to pump protons to one side of the membrane. The protons then flow back through ATP synthase, driving ATP production. The process is similar to pumping water uphill to store potential energy and then using the returning flow to turn a turbine. ATP is the form of energy cells can use directly for muscle contraction, nerve signaling, material transport, repair, and synthesis.

Structure and function are interconnected from the outset. The shape of cristae influences how respiratory-chain complexes are arranged, while the integrity of the inner membrane determines whether the proton gradient can be maintained. The electrical potential across the membrane contributes to ATP production, helps mitochondria take up calcium ions, and supports the import of certain proteins into mitochondria. When the membrane or cristae sustain ongoing damage, the consequences can extend beyond reduced “power output” to calcium handling, protein import, and damage recognition.[1][3]

Human mitochondria contain more than a thousand proteins. Most are encoded by nuclear DNA, synthesized first in the cytoplasm, and then imported into mitochondria through targeting sequences and translocation machinery in the membrane. This is the process of protein import described above; some import into the matrix or inner membrane depends on membrane potential. Mitochondria also contain their own DNA, but mitochondrial DNA serves a distinct coding role: it encodes 13 oxidative-phosphorylation-related polypeptides, 22 transfer RNAs, and 2 ribosomal RNAs.[1][3] The two genomes must work together for mitochondria to carry out their own protein synthesis and maintain stable energy production.

2. When Energy Supply Slows, the Reserve of the Entire Maintenance Chain Narrows

Mitochondria are not fixed, isolated batteries inside cells. They fuse and divide. Fusion allows different mitochondria to share some of their contents, helping the network cope with short-term stress; fission can isolate regions in poorer condition and prepare them for further processing. Mitochondria with persistently low membrane potential or more severe damage may also be recognized by mitophagy, enclosed, and sent for degradation.[5][6]

This maintenance system depends on a relay of coordinated steps. Excessive fission can fragment the network; persistently excessive fusion may make damaged regions harder to isolate in time; and when clearance cannot keep pace with the appearance of damage, inefficient mitochondria remain in the cell for longer. More importantly, recognition, transport, degradation, and rebuilding all require energy themselves. When old components cannot be processed before new demands arrive, cells can shift from adapting with reserve capacity to simply managing to keep up.[1]

Human data provide one observable window into this process. Short and colleagues studied 146 healthy adults aged 18–89 and found that the rate of mitochondrial ATP production in skeletal muscle declined by an average of about 8% per decade; after adjustment for mitochondrial protein abundance, the decline was still about 5%. Maximal oxygen uptake showed a similar age-related trend, and mitochondrial ATP production rate was correlated with maximal oxygen uptake.[4]

This was a cross-sectional study comparing different age groups. It cannot show that every individual declines at the same rate, nor can it fully exclude the influence of physical activity, body composition, or health status. Its greater value is in illustrating the idea of “reserve”: mitochondria do not usually stop working abruptly with age. A more common change is that the room available for adjustment and compensation under the same workload may gradually become smaller.

3. Mitochondrial DNA: Genetic Code in Its Proper Place, an Alarm When Misplaced

Mitochondrial DNA is first and foremost a set of genetic information. It encodes some of the core subunits of the respiratory chain and provides the RNA required for mitochondrial synthesis of these polypeptides. Multiple copies are present within mitochondria, where they combine with associated proteins to form nucleoid structures. Disruption in replication, packaging, or repair can affect energy conversion.[1]

When mitochondrial membranes are damaged, or when damaged mitochondria are not cleared in time, some mitochondrial DNA can enter the cytoplasm or extracellular space. For the innate immune system, DNA appearing in a location where it does not normally belong is itself a danger signal. It can activate pathways such as cGAS–STING and promote interferon- and inflammation-related responses.[7] Genetic material normally involved in energy production can therefore become part of the cell’s outward stress signal.

A moderate, short-lived warning can help mobilize clearance and repair. When alarms recur and fail to resolve, however, the local environment may remain in a state of low-grade inflammation. Inflammation and oxidative stress can then continue to affect mitochondrial membranes, proteins, and DNA, creating mutually reinforcing feedback. Mitochondria therefore connect changes in energy metabolism with immune communication, making the timely resolution of damage an important clue for understanding aging.

4. Repair, Pause, or Exit: How Mitochondrial State Helps Shape Cell Fate

Cells have more than one way to respond to stress. When damage is limited and resources remain sufficient, a cell can reduce some synthesis and proliferation activities and redirect energy toward repair, antioxidant defenses, and autophagy. When stress persists and continued division carries greater risk, some cells enter cellular senescence: they stop dividing while remaining metabolically active and altering the signals they secrete. When damage becomes severe, changes in mitochondrial membrane permeability and related proteins can also promote programmed cell death.[1][8]

Both “pausing” and “exiting” can be protective in the short term. A pause helps prevent damaged cells from continuing to replicate, while programmed cell death can remove cells that are too compromised to recover. Problems arise when these processes fail to resolve cleanly. Senescent cells that accumulate over time can release inflammatory factors, proteases, and extracellular-matrix remodeling signals, changing the working environment of neighboring cells. If dead cells are not cleared promptly, local warning signals may also persist.[8]

The progression from individual cells to tissue-level effects then becomes easier to see. One cell pausing may help protect the tissue; when increasing numbers of cells remain paused for long periods, the tissue has fewer functional units available. Persistent inflammatory and matrix-related signals in the surrounding environment can also make stem-cell renewal, immune clearance, and tissue repair harder to coordinate. Mitochondria do not determine aging on their own, yet they participate in the cellular decision of whether to keep working, temporarily pause, or exit in an orderly manner.

5. Why Mitochondria Have Become Central to Aging Research

Here, “central” means that many pathways converge on mitochondria; it does not imply that mitochondria alone cause every age-related change. Genomic stability affects components of the respiratory chain, nutrient sensing determines whether resources are directed toward growth or maintenance, autophagy removes inefficient components, NAD+ and redox status connect energy metabolism with stress signaling, and cellular senescence and inflammation transmit local changes to surrounding tissues.[1][2] For more detail, see our series “Why the Body Gradually Loses Its Capacity to Recover.”

These pathways also feed back on one another. Impaired electron transport can increase oxidative stress; oxidative and inflammatory signals can continue to damage membranes and DNA; clearing damaged mitochondria requires energy; and insufficient clearance can further weaken energy production. What the review ultimately emphasizes is a systemic decline in adaptive capacity: early changes may be compensatory, but when they persist too long or cannot be resolved, the compensation itself can become a burden.[1]

This also reminds us to interpret “mitochondrial health” cautiously. A single episode of fatigue, one blood marker, or the concentration of one compound cannot represent the state of an entire mitochondrial network. Research needs to examine molecular changes, whether a compound actually reaches the target tissue, whether mitochondrial function changes, and whether those changes translate into activity capacity or other human outcomes.

6. From Mechanism to Nutritional Supplementation: Three Evidence Thresholds Must Be Crossed

Regular physical activity, sufficient sleep, a complete diet, and management of chronic health issues can influence mitochondrial workload and renewal from different directions. Dietary supplements can provide stable, quantifiable nutritional inputs, but at least three questions must be answered in sequence: Can the compound be absorbed by the human body? Can it enter target cells and mitochondria? And can it ultimately change reproducible functional outcomes in humans?

Ergothioneine is one of the dietary supplement ingredients drawing attention in mitochondrial research.[9] In 2024, Fong and colleagues used mass spectrometry to directly demonstrate that ergothioneine can enter and accumulate in mitochondria.[10] A 2025 study published in Cell Metabolism proposed a more specific mechanism: after exercise training, ergothioneine increased in mouse skeletal-muscle mitochondria and directly bound to 3-mercaptopyruvate sulfurtransferase (MPST). MPST participates in sulfur-containing compound conversion and hydrogen-sulfide-related metabolism. In the cell and mouse experiments reported in that study, this pathway was linked to changes in mitochondrial respiration and exercise performance.[11] The work offers an experimental explanation of how ergothioneine may act on mitochondria.

Existing human research first addresses absorption. In a double-blind, placebo-controlled study, 45 healthy adults received 5 mg or 25 mg of pure ergothioneine per day, or placebo, for 7 days. Both doses increased blood ergothioneine levels, while urinary excretion was less than 4% of the ingested amount.[12] These findings support the short-term absorption and retention of ergothioneine in humans and provide a basis for further research on ergothioneine in human mitochondria.

Coenzyme Q10 is located in the inner mitochondrial membrane. It is an important carrier that transfers electrons from respiratory-chain complexes I and II to complex III, and it also contributes to maintaining redox balance within the membrane.[3] To determine whether oral supplementation actually reaches mitochondrial biology, target tissues need to be examined directly. A 2026 randomized, double-blind, placebo-controlled trial enrolled 54 healthy, regularly active adult men who received either 300 mg of reduced coenzyme Q10 (ubiquinol) per day or placebo for 6 weeks. Supplementation increased plasma coenzyme Q10, and muscle biopsies showed some improvement in the coupling efficiency of complex-I-related respiration. However, there were no between-group differences in maximal exercise capacity, oxygen-uptake kinetics, or time to exhaustion during constant-load exercise. The value of this study is that it directly measured skeletal-muscle mitochondria in humans, showing that molecular and mitochondrial-level changes may occur before perceptible changes in exercise performance; the two should not be treated as equivalent.[13]

Research in older adults provides additional clues at the functional level. A 2025 randomized, double-blind trial enrolled 38 sedentary adults aged 65–75. Both groups completed 8 weeks of high-intensity interval training; one group also received 100 mg of coenzyme Q10 per day, while the other received placebo. Compared with training alone, the coenzyme Q10 group showed greater improvement in the five-times sit-to-stand and 30-second sit-to-stand tests, suggesting possible additional support for rising from a seated position and repeated lower-limb force production. No additional advantage was observed for grip strength, balance, timed up-and-go performance, or six-minute walking distance.[14] The sample was small, and coenzyme Q10 was used together with exercise training. The results are therefore best interpreted as suggesting that coenzyme Q10 may help some older adults adapt to training, rather than as evidence that coenzyme Q10 alone reverses aging. Taken together, the two studies point to a more useful question: whether coenzyme Q10 has practical value depends on formulation, dose, duration of use, baseline status, and whether a study measures mitochondrial efficiency or whole-body function.

Conclusion: Understanding Mitochondria Means Understanding How the Body Reconnects Its Recovery Rhythm

Mitochondria sit at the center of aging research because they connect multiple pathways. The inner membrane and cristae support energy conversion; fusion, fission, and mitophagy maintain the network; mitochondrial DNA stores genetic information and can also trigger alarms when it appears in abnormal locations; and cell-fate decisions carry local changes into tissue-level effects.

As we age, one of the body’s core challenges is the gradual narrowing of its coordination reserve. The resilience that SUPER-SYN focuses on is reflected here as well: after activity, stress, and everyday demands, can energy supply keep pace, can damage be cleared, can repair materials reach where they are needed, and can warning signals gradually quiet down once the task is over?

Understanding a mitochondrial study requires looking at the mechanism, study population, dose, duration, target tissue, and real functional outcomes at the same time. Preserving these layers helps place scientific findings back into everyday life and brings each judgment about “anti-aging” or “improving mitochondria” closer to the evidence itself.

References

  1. Marei HE. Mitochondria at the heart of aging: structure, function, and failure. Journal of Translational Medicine. 2026;24:716. doi:10.1186/s12967-026-08047-8.
  2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243-278. doi:10.1016/j.cell.2022.11.001.
  3. Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nature Cell Biology. 2018;20(7):745-754. doi:10.1038/s41556-018-0124-1.
  4. Short KR, Bigelow ML, Kahl J, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proceedings of the National Academy of Sciences of the USA. 2005;102(15):5618-5623. doi:10.1073/pnas.0501559102.
  5. Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337(6098):1062-1065. doi:10.1126/science.1219855.
  6. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Current Biology. 2018;28(4):R170-R185. doi:10.1016/j.cub.2018.01.004.
  7. West AP, Khoury-Hanold W, Staron M, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015;520(7548):553-557. doi:10.1038/nature14156.
  8. Wiley CD, Campisi J. From ancient pathways to aging cells—connecting metabolism and cellular senescence. Cell Metabolism. 2016;23(6):1013-1021. doi:10.1016/j.cmet.2016.05.010.
  9. Gründemann D, Harlfinger S, Golz S, et al. Discovery of the ergothioneine transporter. Proceedings of the National Academy of Sciences of the USA. 2005;102(14):5256-5261. doi:10.1073/pnas.0408624102.
  10. Fong ZW, Cheah IK, Tan YSL, et al. Ergothioneine and mitochondria: an important protective mechanism? Biochemical and Biophysical Research Communications. 2024;726:150269. doi:10.1016/j.bbrc.2024.150269.
  11. Sprenger HG, Mittenbühler MJ, Sun Y, et al. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST. Cell Metabolism. 2025;37(4):857-869.e9. doi:10.1016/j.cmet.2025.01.024.
  12. Cheah IK, Tang RMY, Yew TSZ, Lim KHC, Halliwell B. Administration of pure ergothioneine to healthy human subjects: uptake, metabolism, and effects on biomarkers of oxidative damage and inflammation. Antioxidants & Redox Signaling. 2017;26(5):193-206. doi:10.1089/ars.2016.6778.
  13. Acton JP, et al. Effect of six weeks ubiquinol supplementation on mitochondrial respiratory function and exercise capacity in healthy males: a randomised double-blind placebo-controlled trial. European Journal of Applied Physiology. Published online June 6, 2026. doi:10.1007/s00421-026-06275-w.
  14. Bagheri N, Kargarfard M, Bagheri R, Dutheil F. Effects of coenzyme Q10 supplementation on physical function adaptations to high-intensity interval training in older adults: a randomized controlled trial. Nutrients. 2025;17(24):3959. doi:10.3390/nu17243959.