Mitochondria and energy

In depth

Mitochondria and energy

⏱ 3 min read

Mitochondria are the energy-producing organelles inside practically all cells of the human body (with the exception of mature erythrocytes): the mitochondrial respiratory chain converts the chemical energy of nutrients (glucose, fatty acids, ketone bodies, amino acids) into ATP, the universal energy currency that sustains muscle contraction, nerve conduction, protein synthesis, ion transport, and practically any active cellular process; the tissues with the highest energy demand (brain, heart, skeletal muscle, liver, kidney) have the highest mitochondrial densities, and they are precisely the tissues whose dysfunction produces the most serious clinical syndromes when mitochondria fail.

Why mitochondrial function matters beyond fatigue

Mitochondrial dysfunction has been consolidated over the last decade as one of the central mechanisms of cellular aging and of multiple chronic diseases:

• Unexplained fatigue and exercise intolerance: the most obvious manifestations.
• Sarcopenia and frailty in older adults: muscle loses functional mitochondria with age.
• Neurodegeneration (Parkinson's, Alzheimer's, ALS): neuronal mitochondrial dysfunction is a documented pathological component.
• Heart failure: the myocardium needs massive energy production.
• Insulin resistance and type 2 diabetes: muscle mitochondrial dysfunction is one of the mechanisms.
• Nonalcoholic fatty liver disease: hepatic mitochondrial dysfunction contributes.
• Chronic fatigue syndrome and fibromyalgia: with growing mechanistic backing for a mitochondrial component.

Mitochondrial biogenesis: how new mitochondria are made

The body can continuously generate new mitochondria and eliminate defective ones (mitophagy); the balance between biogenesis and mitophagy determines net mitochondrial health. The main activators of mitochondrial biogenesis include:

• Aerobic exercise: the most potent and best-documented stimulus. It activates PGC-1alpha, the master transcriptional coactivator of mitochondrial biogenesis.
• Modest caloric restriction: activates AMPK and sirtuins, which stimulate biogenesis.
• Intermittent fasting: similar effects.
• Cold exposure: activates thermogenesis and biogenesis in brown adipose tissue.
• Controlled hypoxia (altitude, intermittent training): induces mitochondrial adaptations.
• Some compounds: PQQ, urolithin A, spermidine, resveratrol (although the clinical evidence varies).

Interventions with clinical backing

Coenzyme Q10 (ubiquinol): an essential cofactor of the mitochondrial respiratory chain. Adequate intake improves ATP production in tissues with mitochondrial dysfunction. Indications with backing: heart failure (Q-SYMBIO study), statin myopathy, migraine prophylaxis, fertility (semen analysis).

Creatine: increases the availability of muscle and brain phosphocreatine, improving bioenergetic capacity. Documented benefits in muscle strength, cognition under stress (sleep deprivation, hypoxia), muscle aging, and possibly neuroprotection.

Magnesium: an essential cofactor for more than 300 enzymatic reactions, including the synthesis and stability of ATP (ATP-Mg2+); subclinical deficiency is common.

Vitamin B12, folate, B6: cofactors of energy metabolism; subclinical deficiencies cause fatigue even before anemia.

Iron: deficiency causes fatigue and mitochondrial dysfunction; it is important to distinguish between established iron-deficiency anemia (which requires treatment) and low ferritin without anemia (which can also cause fatigue).

L-carnitine and acetyl-L-carnitine: transporters of fatty acids into the mitochondria; clinical backing in age-related fatigue and in some mitochondrial myopathies.

Nicotinamide riboside (NR) and NMN: NAD+ precursors with growing clinical research for mitochondrial aging, although definitive human data are still in development.

Urolithin A: with growing data on mitophagy and improved muscle function in older adults.

PQQ (pyrroloquinoline quinone): stimulates mitochondrial biogenesis via PGC-1alpha with modest clinical data.

Alpha-lipoic acid: a mitochondrial cofactor with antioxidant effects; clinical backing in diabetic neuropathy.

The forgotten factor: sleep

During deep sleep, mitochondria enter repair and recycling mode; chronic sleep deprivation leads to the accumulation of dysfunctional mitochondria and a net deterioration of cellular bioenergetic function. Sufficient, good-quality sleep is probably the most underrated "mitochondrial intervention."

Exercise as mitochondrial medicine

If only one intervention could be recommended to optimize mitochondrial function, it would be regular physical exercise combining aerobic and strength training. Moderate-to-intense aerobic exercise (4-6 sessions/week) stimulates muscle mitochondrial biogenesis; high-intensity interval training (HIIT) produces particularly efficient mitochondrial adaptations; strength training preserves muscle mass and therefore total body mitochondrial density.

When to see a doctor

Severe fatigue of unclear cause lasting weeks or months, progressive muscle weakness, unexplained exercise intolerance, and multisystem symptoms (neurological + muscular + cardiac) suggesting primary mitochondrial disease require medical evaluation. Hereditary mitochondrial syndromes (MELAS, MERRF, others) are rare but exist and require specialized treatment.

The reasonable conclusion

Optimal mitochondrial function is the result of a set of sustained habits (regular exercise, adequate sleep, a nutrient-rich diet, optional moderate intermittent fasting, exposure to controlled hormetic stress) plus, when appropriate, specific supplements with backing (CoQ10, creatine, magnesium, B12/folate/B6 if deficient, urolithin A in older adults). "Mitochondrial supplements" as a commercial category are useful only as modest complements to the structural interventions.

References

1. Mortensen, S.A. et al. (2014). The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO. JACC Heart Fail 2, 6. doi:10.1016/j.jchf.2014.06.008
2. López-Lluch, G. et al. (2008). Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA 103, 6. doi:10.1073/pnas.0510452103
3. Andreux, P.A. et al. (2019). The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 6. doi:10.1038/s42255-019-0073-4
4. Rae, C. et al. (2003). Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci 270, 1529. doi:10.1098/rspb.2003.2492
5. Sun, N.; Youle, R.J.; Finkel, T. (2016). The mitochondrial basis of aging. Mol Cell 61, 5. doi:10.1016/j.molcel.2016.01.028