Mitochondria: Why Cellular Energy Matters Clinically

Fatigue is among the most common reasons patients seek help, and among the most frustrating for practitioners, because it has so many possible causes and so rarely a single one. Somewhere beneath most of them lies a common pathway: the ability of cells to produce and use energy. Mitochondria are central to that pathway, which is why they appear so often in functional medicine discussions. They are also a subject in which fascinating science and inflated claims sit side by side. This article aims to give practitioners the science and a clear sense of where it currently supports clinical action.

More than powerhouses

Mitochondria are often described as the powerhouses of the cell, and energy production is indeed their best known role. Through the citric acid cycle and oxidative phosphorylation, they convert fuel from carbohydrate and fat into adenosine triphosphate, ATP, the molecule that powers almost every energy requiring process. Tissues with high energy demands, such as heart muscle, skeletal muscle, the brain, the retina and the kidney, contain especially large numbers.

But mitochondria do much more:

• They generate reactive oxygen species, which at low levels act as important signals and at high levels can damage cells.
• They help regulate calcium within cells, which is essential for muscle contraction and nerve signalling.
• They produce heat, particularly in brown fat.
• They control apoptosis, the programmed death of damaged cells.
• They participate in the synthesis of steroid hormones and haem.
• They communicate with the nucleus and influence gene expression and immune responses.

Mitochondria also have their own small circle of DNA, inherited almost entirely from the mother, which encodes some of the proteins of the energy producing machinery. The rest are encoded in the nucleus. This dual genetic control is the basis of the very varied inheritance of mitochondrial disease.

Primary mitochondrial disease

Primary mitochondrial diseases are genetic disorders caused by variants in mitochondrial or nuclear DNA that impair mitochondrial function. Collectively they are among the more common inherited metabolic disorders, affecting roughly one in several thousand people, but each individual condition is rare. They typically affect high energy tissues and can present at any age with combinations of muscle weakness, exercise intolerance, ptosis and eye movement problems, hearing loss, diabetes, cardiomyopathy, seizures, stroke like episodes and developmental problems.

Primary mitochondrial disease requires specialist diagnosis, usually involving genetic testing and sometimes muscle biopsy, and specialist management. Practitioners should consider referral when a patient has unexplained involvement of several high energy organs, a maternal family history of similar problems, or unusual reactions to certain medicines.

Secondary mitochondrial dysfunction

Much more common, and more relevant to everyday practice, is mitochondrial dysfunction secondary to other conditions and exposures. Here, mitochondria are genetically normal but their number, efficiency or regulation is impaired.

Physical inactivity

Muscle mitochondria are highly responsive to use. Inactivity reduces mitochondrial content and capacity, contributing to reduced exercise tolerance and insulin resistance.

Insulin resistance and excess nutrients

Chronic excess of fuel, particularly with inactivity, is associated with reduced mitochondrial efficiency in muscle and liver and increased production of reactive oxygen species. The direction of causation between mitochondrial dysfunction and insulin resistance remains debated; each probably worsens the other.

Ageing

Mitochondrial function declines with age, partly through accumulated damage and partly through reduced activity. How much of the decline is inevitable and how much reflects inactivity is an active research question; trained older adults retain substantially higher mitochondrial capacity than sedentary peers.

Medicines

Several medicines affect mitochondria. Some older antiretroviral drugs caused mitochondrial toxicity. Certain aminoglycoside antibiotics can cause hearing loss in people carrying a specific mitochondrial DNA variant. Sodium valproate requires particular caution in some mitochondrial disorders. Metformin acts partly through effects on mitochondrial energy metabolism, although this contributes to its therapeutic action rather than causing harm in most people. Statins have been proposed to reduce coenzyme Q10 levels, which is discussed below.

Chronic disease and illness

Mitochondrial dysfunction has been described in heart failure, chronic kidney disease, neurodegenerative diseases, some autoimmune conditions and after severe illness. In many of these it is one contributor among several rather than a primary cause.

What this means for fatigue

It is tempting to attribute unexplained fatigue to mitochondrial dysfunction. That may sometimes be part of the picture, but the label rarely helps unless it points to something modifiable. In practice, the most common and treatable causes of fatigue act upstream of mitochondria or alongside them: iron deficiency, B12 deficiency, hypothyroidism, poor sleep and sleep apnoea, depression, deconditioning, insulin resistance, medicines and chronic stress. Assessing and addressing these comes first. The energy system of the matrix is a place to organise findings, not a diagnosis.

The most powerful intervention

If there is one intervention with strong evidence for improving mitochondrial health, it is exercise. Endurance training increases mitochondrial content and function in muscle through a coordinated programme of mitochondrial biogenesis, regulated in part by a transcriptional coactivator known as PGC 1 alpha. High intensity interval training produces similar adaptations in shorter time. Resistance training preserves muscle mass, the tissue in which much of this capacity resides. These changes occur in older adults and in people with chronic disease, as well as in the young and fit.

For fatigued patients, the practical challenge is dosing. Too little activity perpetuates deconditioning; too much, too soon, can worsen symptoms, particularly in people with post exertional symptom exacerbation. Graded, individualised programmes that respect the patient’s response are essential, and in conditions such as myalgic encephalomyelitis or chronic fatigue syndrome, specialist guidance on pacing should be followed.

Other factors that support mitochondrial function

• Adequate sleep, which influences metabolic regulation and repair.
• Nutritional adequacy, particularly iron, B vitamins, magnesium and other cofactors required for energy metabolism. Deficiency impairs function; correcting deficiency helps, but excess does not provide additional benefit.
• Avoiding chronic energy excess, since weight loss in people with obesity improves markers of mitochondrial function.
• Avoiding smoking and excessive alcohol, which damage mitochondria.

Mitochondrial supplements: what the evidence shows

A number of supplements are marketed for mitochondrial support. The evidence is summarised honestly below.

High doses of antioxidants deserve particular caution. Because reactive oxygen species act as signals for some of the beneficial adaptations to exercise, some studies have found that high dose antioxidant supplements blunted training adaptations. More antioxidant is not necessarily better.

Testing

Routine laboratory tests do not measure mitochondrial function directly. Lactate levels, creatine kinase and organic acid profiles can support investigation of suspected primary mitochondrial disease in specialist settings. Commercial tests claiming to assess mitochondrial function in the general population have limited validation, and their results rarely change management compared with a careful history and assessment of common causes of fatigue.

An illustrative case

A 58 year old man reports 2 years of declining stamina since retiring from a physical job. He becomes breathless on stairs, has gained weight around his waist and has developed prediabetes. His blood count, thyroid function, B12 and ferritin are normal. He has read about mitochondrial supplements and bought several.

His assessment points to deconditioning and insulin resistance as the main drivers of reduced energy capacity. The plan is a progressive walking programme building to brisk walking most days, 2 weekly sessions of resistance exercise, an improvement in diet quality and a gradual reduction in evening alcohol. The supplements are reviewed; none is harmful, but none is likely to add much, and he chooses to stop them. Over 4 months his exercise tolerance improves markedly, his waist shrinks and his HbA1c falls. His mitochondria responded to the stimulus they have always responded to.

Keeping mitochondria in perspective

Mitochondrial biology illuminates why energy is so central to health and why exercise, sleep, nutrition and metabolic health matter so much. It does not, for most patients, point to a special test or a special supplement. It points to the fundamentals, delivered well and dosed carefully.