Hallmark 7: Mitochondrial Dysfunction
Meet the mitochondria
Every cell in our body contains hundreds to thousands of mitochondria. In biology class they were described as “powerhouses” because they burn fats and sugars and use the released electrons to produce adenosine triphosphate (ATP) - the molecule that powers almost all cellular work. Modern research has broadened this view.
Mitochondria are not static power plants; they are more like a network of mini-batteries that constantly fuse and divide to match local energy demand. They can even move within a cell toward areas where energy is needed. This flexibility, along with a unique double-membrane structure, allows mitochondria to do much more than produce ATP. They regulate calcium concentrations, generate heat in brown fat, help decide when a cell should die, and act as signalling hubs through the production of reactive oxygen species (ROS). Roughly 95 % of the cell’s ATP is produced inside mitochondria [1], so even modest impairment in their function can be felt throughout the body.
How mitochondrial dysfunction happens and why it matters in ageing
A young person’s mitochondria are well-maintained power plant, however, As we age, several changes accumulate in the maintenance procedure:
Gradual damage to mitochondrial DNA and proteins
The mitochondria actually have their own unique DNA, called mitochondrial DNA (mtDNA). This small set of genetic instructions helps the mitochondria produce the energy our bodies need to function. Unlike the main DNA found in the cell’s nucleus, mtDNA sits right next to where energy production happens inside the mitochondria. During this process, tiny, harmful molecules called reactive oxygen species (ROS) are naturally created, and they can damage mtDNA.
MtDNA doesn’t have the same protective proteins or strong repair systems as nuclear DNA, therefore it’s much more vulnerable and develops mutations up to 15 times more often. Over time, these mutations build up, especially in energy-hungry parts of the body like the brain, muscles, and heart.
When too many parts of the energy-making machinery are damaged, the mitochondria start producing less energy (ATP) and even more ROS. This creates a vicious cycle, where energy production drops while damage keeps increasing.
Disrupted quality control and “house-keeping”
While a small amount of reactive oxygen species (ROS) is normal and even helpful for cell signaling, problems arise when damaged mitochondria produce too much. As excess ROS builds up, it starts to harm the cell by damaging proteins, fats, and DNA, and triggering inflammation.
This kind of mitochondrial dysfunction also means less energy (ATP) is produced, and the cell’s normal systems for regulating repair and programmed cell death can become disrupted. Over time, this creates a downward spiral of declining energy, rising oxidative stress, and poor cellular health.
A clear example of this can be seen in the skin. Ultraviolet (UV) radiation from the sun directly damages mitochondrial DNA in skin cells, leading to excessive ROS production. This causes further mitochondrial damage, eventually pushing cells into senescence (a state where they stop dividing and functioning properly) or cell death. These changes contribute to photoaging, such as wrinkles and loss of elasticity, and increase the risk of skin cancers [2].
Accumulation of ROS and inflammatory signals
ROS are often portrayed as purely harmful, but at low levels they act as signalling molecules. With age, however, the balance tips. Excessive ROS from dysfunctional mitochondria oxidise proteins, lipids and DNA and activate inflammatory pathways. Studies show that mitochondrial dysfunction is associated with reduced ATP production, altered regulation of apoptosis and increased ROS and defective calcium signalling. Continuous ultraviolet radiation (UVR) exposure is a striking example: UVR induces mitochondrial DNA mutations and excessive ROS in skin cells, leading to loss of membrane potential, apoptosis and cellular senescence and contributing to photo-aging and skin cancers [2].
Crosstalk with other hallmarks of ageing
Mitochondrial problems don’t happen in isolation - they are closely linked to other key drivers of aging, like DNA damage, shortening of protective chromosome ends (telomeres), changes in how genes are switched on and off (epigenetic changes), and the buildup of senescent cells (old, non-functioning cells).
When mitochondria are damaged, they can release bits of DNA and proteins that act as danger signals, triggering inflammation and further spreading cellular stress. This creates a chain reaction where different aging processes feed into each other, speeding up the decline of tissues throughout the body.
Future prospects
Research into protecting and restoring mitochondrial function is advancing rapidly. Here are some of the most promising areas:
1. Boosting NAD⁺ levels
NAD⁺ is a molecule essential for energy production and cell signaling, but its levels drop with age and this decline can contribute to mitochondrial stress and reduced efficiency. Supplements like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) can raise NAD⁺ levels, improving mitochondrial health and activating protective enzymes like sirtuins and AMPK. Early studies show potential benefits for metabolism and brain health, and several human trials are underway.
2. Mitochondria-targeted antioxidants
Most traditional antioxidants don’t reach mitochondria where damage happens. New compounds, like Mito-TEMPO, MitoQ, and SkQ1, are specially designed to target mitochondria. These have shown promise in reducing harmful molecules (ROS) and protecting against conditions like heart disease, neurodegeneration, and even sun damage.
3. Natural compounds
Certain foods contain natural compounds that support mitochondrial health, such as resveratrol (grapes), quercetin(onions and apples), curcumin (turmeric), and coenzyme Q10. While normal diets may not provide enough for therapeutic effects, these compounds may still help reduce oxidative stress and improve mitochondrial function when combined with a healthy lifestyle.
4. Exercise and exercise mimetics
Regular physical activity is one of the best ways to keep mitochondria healthy. Exercise encourages the growth of new mitochondria and improves their quality. Scientists are also studying “exercise mimetics” - drugs designed to mimic these effects - but none match the full benefits of real physical activity.
5. Advanced therapies
In the future, cutting-edge approaches like mitochondrial transfer (replacing damaged mitochondria with healthy ones) and gene editing to fix mutations in mitochondrial DNA may become possible. These are still experimental but show how far mitochondrial research has come.
What you can do to support your mitochondrial health
Scientific advances are exciting, but everyday choices remain the foundation of mitochondrial well-being. The following strategies are supported by research, though individual responses vary and anyone with health conditions should consult a professional before making major changes.
Move more - activate your cellular clean-up crew
Moderate endurance exercise – brisk walking, cycling or swimming – triggers mitochondrial biogenesis and mitophagy. It enhances the PGC-1α/AMPK/SIRT1 pathway [5] and increases fission and autophagy markers, thereby renewing mitochondrial populations [6]. Strength training also supports mitochondrial function, particularly in muscle. Aim for a mix of aerobic and resistance activities that you enjoy and can sustain.
Feed your mitochondria wisely
A diet rich in fruits, vegetables, whole grains, nuts and fish provides vitamins, minerals and antioxidants that support mitochondrial enzymes and neutralise excess ROS. Bioactive compounds such as resveratrol, quercetin, coenzyme Q10, curcumin and astaxanthin have been shown to ameliorate mitochondrial dysfunction [5]. Healthy fats (e.g., those found in olive oil and oily fish) are important substrates for mitochondrial β-oxidation. Avoiding excessive caloric intake and highly processed foods reduces mitochondrial stress.
Consider intermittent fasting or caloric restriction under guidance
Periods of reduced caloric intake activate protective pathways. Calorie restriction (without malnutrition) and various forms of intermittent fasting reduce cell proliferation, decrease ROS production, activate AMPK and sirtuins and stimulate mitophagy and antioxidant expression [7]. They lower levels of insulin and inflammatory mediators and improve metabolic health. Although long-term data in humans are still emerging, short-term fasting (e.g., 12–16 h overnight fasts) is widely practised. Always seek medical advice before starting fasting
Disclaimer: Fasting isn’t a one-size-fits-all approach. For women especially, overdoing it - particularly alongside stress, intense exercise, or at certain points in the menstrual cycle - can sometimes backfire. Think of fasting as a flexible tool, not a strict rule: start gently, stay adaptable, and listen to your body. When in doubt, consult a healthcare professional to find what works best for you.
Protect your skin - and your mitochondria
UV radiation is a major external driver of mitochondrial damage in skin cells. Continuous UV exposure generates ROS, causes mtDNA mutations and reduces respiratory capacity, leading to photo-aging [2]. Regular use of broad-spectrum sunscreen, protective clothing and seeking shade during peak sun hours helps preserve mitochondrial integrity in the skin and reduce wrinkle formation and cancer risk.
Prioritise sleep, avoid smoking and manage stress
Adequate sleep allows mitochondria to repair and recharge; chronic sleep deprivation has been linked to metabolic dysfunction. Smoking introduces toxins that directly impair mitochondrial respiration and increase ROS. Chronic psychological stress raises cortisol and inflammatory mediators that can harm mitochondria. Mindfulness practices, social connections and regular sleep routines support overall mitochondrial and systemic health.
Conclusion
Mitochondria sit at the centre of energy, signalling and cellular resilience. While ageing and stress can compromise their function, they remain adaptable. Through regular activity, balanced nutrition, intermittent fasting and sun protection, supported by advances in emerging therapies, we can sustain mitochondrial health and promote healthier ageing.
References
[1] Somasundaram I, Jain SM, Blot-Chabaud M, Pathak S, Banerjee A, Rawat S, Sharma NR, Duttaroy AK. Mitochondrial dysfunction and its association with age-related disorders. Front Physiol. 2024 Jul 2;15:1384966. doi: 10.3389/fphys.2024.1384966
[2] Yuan X, Li H, Lee JS, Lee DH. Role of Mitochondrial Dysfunction in UV-Induced Photoaging and Skin Cancers. Exp Dermatol. 2025 May;34(5):e70114. doi: 10.1111/exd.70114
[3] Sharma A, Chabloz S, Lapides RA, Roider E, Ewald CY. Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023 Jan 14;15(2):445. doi: 10.3390/nu15020445
[4] Shetty S, Deepak K, Tambe PK, Udupi A, Bharati S. Mito-TEMPO Demonstrates Protective Effect Against Ultraviolet Radiation-Induced Skin Damage in Wistar Rats. Photodermatol Photoimmunol Photomed. 2024 Nov;40(6):e13010. doi: 10.1111/phpp
[5] Kim MB, Lee J, Lee JY. Targeting Mitochondrial Dysfunction for the Prevention and Treatment of Metabolic Disease by Bioactive Food Components. J Lipid Atheroscler. 2024 Sep;13(3):306-327. doi: 10.12997/jla.2024.13.3.306. Epub 2024 Jun 17
[6] Balan E, Schwalm C, Naslain D, Nielens H, Francaux M, Deldicque L. Regular Endurance Exercise Promotes Fission, Mitophagy, and Oxidative Phosphorylation in Human Skeletal Muscle Independently of Age. Front Physiol. 2019 Aug 22;10:1088. doi: 10.3389/fphys.2019.01088
[7] Mehrabani S, Bagherniya M, Askari G, Read MI, Sahebkar A. The effect of fasting or calorie restriction on mitophagy induction: a literature review. J Cachexia Sarcopenia Muscle. 2020 Dec;11(6):1447-1458. doi: 10.1002/jcsm.12611
Author: Georgia Pilling
