Mitochondrial Dysfunction and Oxidative Stress: Causes and Clinical Signs

An earlier article described mitochondria and the importance of cellular energy. This article looks at a closely linked concept, oxidative stress, and at what drives mitochondrial dysfunction in everyday practice. Oxidative stress has become one of the most commonly invoked explanations for ageing and chronic disease, and antioxidants are among the most heavily marketed supplements. The science behind these ideas is genuine and fascinating, but the clinical conclusions often drawn from it are not supported by trial evidence.

Reactive oxygen species: signals and threats

Reactive oxygen species, such as superoxide, hydrogen peroxide and hydroxyl radicals, are produced continuously, mainly by mitochondria during energy production and by immune cells fighting infection. For many years they were viewed simply as damaging by products. It is now clear that at low levels they are essential signalling molecules, regulating cell growth, immune responses, insulin signalling and adaptation to exercise.

Problems arise when production exceeds the capacity of antioxidant defences, damaging lipids, proteins and DNA. This imbalance is called oxidative stress. The body’s defences include enzymes such as superoxide dismutase, catalase and glutathione peroxidase, the glutathione system itself, and dietary antioxidants such as vitamins C and E and polyphenols. Selenium, zinc, copper and manganese are needed for antioxidant enzymes.

Hormesis: why a little stress helps

Hormesis describes the phenomenon by which a mild stressor triggers adaptive responses that increase resilience. Exercise is the clearest example: it temporarily increases reactive oxygen species production, which signals muscle cells to build more mitochondria and increase antioxidant enzyme production. In a study in healthy young men, taking high dose vitamins C and E during an exercise programme blocked some of the beneficial effects of exercise on insulin sensitivity and antioxidant defences. Suppressing oxidative signals can therefore suppress adaptation.

What drives oxidative stress and mitochondrial dysfunction

Clinical signs

There is no specific clinical syndrome of oxidative stress. Mitochondrial dysfunction and oxidative stress are mechanisms that contribute to many conditions rather than diagnoses in themselves. Features that suggest a relevant energy problem include fatigue with reduced exercise tolerance, slow recovery after exertion and muscle weakness, but these have many causes. In practice, the conditions associated with oxidative stress, such as diabetes, fatty liver disease, cardiovascular disease and chronic lung disease, are the targets of clinical care.

Primary mitochondrial disease, a rare genetic condition, should be considered when multiple high energy organs are affected, as described in the earlier article.

Measuring oxidative stress

Researchers measure oxidative stress through markers such as F2 isoprostanes, which reflect lipid oxidation, 8 hydroxy deoxyguanosine, reflecting DNA oxidation, and ratios of reduced to oxidised glutathione. These measurements require careful sample handling and specialist methods, and their clinical interpretation in individuals is not established. Commercial oxidative stress panels offered to patients have limited validation, and their results rarely change management.

The antioxidant supplement story

Because oxidative stress is associated with many diseases, it seemed logical that antioxidant supplements would prevent them. Large trials tested this idea.

• Beta carotene increased lung cancer in smokers in 2 large trials.
• Vitamin E did not reduce cardiovascular events in major trials and was associated with increased prostate cancer risk in one large trial.
• A systematic review of antioxidant supplement trials found no reduction in mortality, and possible increases with beta carotene, vitamin E and high dose vitamin A.

Several explanations have been proposed: supplements may interfere with beneficial signalling, may not reach the relevant tissues at the relevant time, may act as pro oxidants in some contexts, and may not replicate the effects of whole foods that contain many compounds acting together.

N acetylcysteine and glutathione

N acetylcysteine, a precursor of glutathione, is an established treatment for paracetamol overdose, where it replenishes glutathione. It has been studied in many other conditions, including chronic obstructive pulmonary disease, where it may reduce exacerbations in some patients, and psychiatric disorders, where results are mixed. Its use outside established indications should be guided by evidence for the specific condition.

What reliably helps

1. Glucose control in diabetes, which reduces oxidative damage and complications.
2. Regular physical activity, which builds mitochondrial and antioxidant capacity through hormesis.
3. Weight management in people with obesity.
4. Stopping smoking and limiting alcohol.
5. A diet rich in vegetables, fruit, legumes, whole grains, nuts and olive oil, which provides antioxidants within whole foods and is associated with lower oxidative stress markers.
6. Correcting deficiencies of selenium, zinc and other cofactors where present.
7. Reducing exposure to air pollution where possible.
8. Treating inflammation at its source.

An illustrative case

A 57 year old man with type 2 diabetes, poor glucose control and early kidney changes takes several antioxidant supplements, including high dose vitamin E and a commercial antioxidant blend, having read that they protect against diabetic complications. He exercises rarely and smokes. The practitioner explains the evidence on antioxidant supplements and focuses the plan on the drivers of oxidative damage in his case: glucose control with his physician, smoking cessation, a progressive walking and strength programme and a Mediterranean style diet. The high dose vitamin E is stopped. A year later his HbA1c has improved substantially, he has stopped smoking and his kidney markers have stabilised. The most effective antioxidant strategy was addressing the sources of oxidative stress.

Beyond antioxidants

Oxidative stress and mitochondrial dysfunction are real and important mechanisms in chronic disease. The evidence shows that the way to address them is not to flood the body with antioxidant supplements, but to reduce the drivers of damage and strengthen the body’s own defences through activity, metabolic health and whole food nutrition.