Mitochondria are the power stations of our cells. In them the body burns sugar and fat with oxygen and obtains almost all the energy it needs. Depending on the tissue, a single cell contains hundreds to thousands of them, most of all in the heart, muscles, brain and liver.
But mitochondria do more than supply energy. They help decide whether a cell divides, whether it matures and rests, or whether it dies. That is why they matter as much for physical performance as for the question of how cancer arises.
Structure and functions
Mitochondria have their own circular genetic material and their own ribosomes; they descend from bacteria that entered our ancestral cells some two billion years ago. They are mobile and changeable: they grow, shrink, divide and fuse with one another again.
Besides energy, they perform a number of other tasks:
- Production of ATP, the energy currency of the cell
- Citric acid cycle (Krebs cycle) and fat burning (beta-oxidation)
- Production of ketone bodies and new glucose
- Urea cycle and amino acid metabolism
- Production of haem, the red pigment of the blood
- Formation of the steroid hormones
- Storage and regulation of calcium
The energy is produced at the inner membrane, which is folded into many cristae. This is where the respiratory chain sits. It needs iron in its iron-sulphur centres, as well as coenzyme Q10, magnesium, manganese, vitamins B1, B2 and B3, pantothenic acid and lipoic acid. A special fat, cardiolipin, is found only in mitochondria: it keeps the cristae in shape, binds the complexes of the respiratory chain together and seals the membrane so that no protons are lost.
Respiration also produces free radicals. In small amounts they act as signals; in excess they cause damage. The cell defends itself with enzymes that need manganese, copper, zinc and selenium. Environmental toxins, heavy metals, certain medicines such as statins and chronic inflammation can put additional strain on the mitochondria, among other things through nitrogen radicals, known as nitrosative stress.
Two routes to energy
Every cell first breaks sugar down to pyruvate within the cell; this is glycolysis. Then the route forks. Without oxygen, pyruvate is fermented to lactate: this is fast but yields only 2 ATP per sugar molecule. With oxygen, pyruvate moves into the mitochondria and is burned completely to carbon dioxide and water: this is slower but yields around 30 ATP.
The fast route serves short, intense exertion, fight or flight. It leads to lactate and acidosis. The route through the mitochondria is the route of endurance; it also burns fat.
Cell division and differentiation
Dividing is the basic state of every cell, as it is for all micro-organisms. In a multicellular body this division has to be held in check so that cells can mature, specialise and do their job. Here the mitochondria play a key role: respiration in the mitochondria promotes the signals that inhibit division. In this way respiration secures the differentiation and the quiescence of the cell.
This can be seen along the path a cell takes through its life. Stem cells and embryonic cells divide rapidly. Their mitochondria are small, round and barely folded, and they obtain their energy mainly from glycolysis. There is a reason for this: a dividing cell needs not only energy but building material for a new cell, and the intermediate products of glycolysis supply it. As the cell matures, it switches over. The mitochondria become more numerous, longer and more folded; the cell respires and rests.
This change goes hand in hand with a second one. The enzyme telomerase, which lengthens the ends of the chromosomes and so allows any number of divisions, is highly active in young, embryonic cells. In mature cells with intact respiration it is hardly active any more.
The mitochondria talk to the nucleus
Mitochondria and the nucleus are in constant exchange. When respiration falters, the mitochondria report this to the nucleus; this is the retrograde response. In the short term it helps the cell survive: the nucleus switches on enzymes that provide energy without oxygen. If the disturbance persists, however, genes such as Myc, Ras, HIF-1α, Akt and mTOR, which drive growth and fermentation, are permanently amplified. More free radicals are formed, and the guardian of the genome, the protein p53, is weakened. The genome becomes unstable.
Apoptosis: orderly cell death
The mitochondria also decide when a cell has to die. If it is too badly damaged, its mitochondria release cytochrome c, which otherwise works in the respiratory chain. In the cytoplasm it sets off a cascade of enzymes, the caspases, and the cell dismantles itself in an orderly way, without inflammation. This is how the body protects itself from diseased cells.
Healthy ageing cells whose respiration fails do not compensate by increasing glycolysis. They die and never become tumour cells. If, on the other hand, a cell manages to replace the missing respiration with fermentation, it escapes this cell death. This is where the path to cancer begins.
Mitochondria and performance
The body has three energy systems that take over from one another. For the first few seconds, the muscle’s store of ATP and creatine phosphate is enough. Up to about two minutes, glycolysis carries the load, producing lactate. Anything longer is done by the mitochondria with oxygen. A golf swing uses almost only the first system; a long-distance run draws around 70 per cent from the third.
The lactate curve
The lactate exercise test shows how well the mitochondria are working. On the ergometer the workload rises in steps, and after each step the lactate in the blood is measured. As long as the mitochondria keep up, it stays low. Beyond a certain workload it rises steeply: the body switches to fermentation. In trained people this rise lies far to the right; with iron deficiency, in smokers, in diabetes and with impaired mitochondria it comes at a low workload.
The curve also shows how to train. Healthy athletes spend 85 to 90 per cent of their training time below 2.4 mmol/l of lactate. In this range endurance grows and fat is burned; higher values belong in short intervals.
Iron
No respiration without iron: it is found in the iron-sulphur centres and cytochromes of the respiratory chain and in around 180 other reactions in the body. Iron deficiency therefore causes tiredness and poor performance, even when haemoglobin is still normal. Cell division needs iron too, because the enzyme that makes the building blocks of DNA cannot work without it.
Radicals as a training stimulus
The free radicals produced during exercise are a signal: they prompt the body to form new mitochondria and to strengthen its own protective enzymes. One study showed that high doses of vitamin C (1000 mg) and vitamin E (400 IU) can cancel out this healthy effect of exercise on glucose metabolism. High-dose antioxidants therefore do not belong right around training.
Source: Ristow M et al., PNAS 2009
Mitochondria and the development of cancer
Radiation, toxins, viruses and chronic inflammation trigger cancer, although their effects are entirely non-specific. How does such a specific process as a tumour arise from them? One answer lies in the mitochondria: all of these influences can disturb the respiration of the cell.
The Warburg effect
As early as the 1920s, Otto Warburg discovered that tumour cells ferment sugar to lactate even when there is enough oxygen. This applies to almost all tumours, whatever tissue they come from. Tumour cells therefore take up far more sugar than healthy cells. This is the basis of the PET scan, which makes tumours visible with labelled sugar.
Tumour cells differ from normal cells not in the amount of energy but in its source. They need roughly as much energy as any cell, but obtain it from fermenting sugar and breaking down the amino acid glutamine rather than from respiration.
When fermentation replaces respiration
In the view of the American researcher Thomas Seyfried, cancer begins with a long phase in which a cell’s respiration is damaged step by step. The cell keeps itself alive by fermentation. At first this is reversible; once respiration is too badly destroyed, it no longer is. A normal cell cannot take this way out, and dies.
This fits what is seen in tumours: the more malignant a tumour, the less normal its mitochondria. They are round, have few cristae, and their cardiolipin is altered. Protons leak back through the inner membrane, producing more radicals and heat instead of energy.
Most researchers regard changes in the genome as the starting point of cancer. The altered energy metabolism, however, is an established hallmark of every tumour and a point of attack for prevention and treatment. In some tumours the defect even lies directly in mitochondrial enzymes.
Sources: Seyfried TN, Shelton LM, “Cancer as a metabolic disease”, Nutr Metab 2010; Pedersen PL 1978; Hanahan D, Weinberg RA, Cell 2011
Assessment and support at the clinic
We test the mitochondria under exertion, because at rest the values are often unremarkable. This includes the lactate exercise test on the ergometer, the blood count, ferritin as a measure of iron stores, and vitamin B12. In addition, we perform a venous blood gas analysis. From it, the research of Dr med. John van Limburg Stirum gave rise to what is known as Mitochondrial Activity, calculated from oxygen, carbon dioxide and lactate.
If something is lacking, we replace it in a targeted way: iron, as an infusion if needed, coenzyme Q10, alpha-lipoic acid, L-carnitine, creatine, vitamins B1, B2, B3 and pantothenic acid, magnesium, manganese and zinc. Just as important are exercise in the right range of the lactate curve, a diet low in sugar, and reducing burdens such as environmental toxins and chronic inflammation.
In cancer, a low-sugar diet, up to a ketogenic diet or fasting, can accompany treatment. It does not replace it and should be medically supervised.