What is mitochondrial disease?


Mitochondrial disease is a collective term for a group of disorders that particularly affect the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems. There are many different types of mitochondrial disease (see Types) It is a complex group of disorders, with many different symptoms and many different causes within the mitochondria.

Our bodies are made up of many different tissues, for example muscle, nerve, and liver. Each tissue is composed of small 'building blocks', called cells, and within each cell are small objects known as mitochondria. The job of these mitochondria is to produce energy. Just like a power generator, they take in fuel (the food we eat) and burn it up to generate energy. If this process fails, the cell cannot function adequately and this can lead to disease. Muscle and brain require a lot of energy, and are often the most severely affected.

The part of mitochondria concerned with energy production is called the respiratory chain. Components (called proteins) of this respiratory chain pathway are produced from a genetic blueprint (the DNA) found either within the mitochondria themselves (mtDNA), or on the chromosomes in what is called the nucleus of the cell.

Mitochondrial disease results from failures of the mitochondria. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. When they fail, less and less energy is generated within the cell. Disease of the mitochondria appears to cause the most damage to parts of the body which need a lot of energy: the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection. If the process of cell injury is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised.

Many mitochondrial disorders, even though they involve the mitochondrial DNA, are sporadic. This means that only one individual in a family is affected - the parents and any children of that person are unaffected. Other mitochondrial disorders are only inherited from the mother. Disorders that arise because of defects within the genes found on chromosomes within the nucleus may be inherited from either parent.


The conventional teaching in biology and medicine is that mitochondria function only as "energy factories" for the cell. This over-simplification is a mistake which has slowed our progress toward understanding the biology underlying mitochondrial disease. It takes about 3000 genes to make a mitochondrion. Mitochondrial DNA encodes just 37 of these genes; the remaining genes are encoded in the cell nucleus and the resultant proteins are transported to the mitochondria. Only about 3% of the genes necessary to make a mitochondrion (100 of the 3000) are allocated for making ATP. More than 95% (2900 of 3000) are involved with other functions tied to the specialized duties of the differentiated cell in which it resides.

These duties change as we develop from embryo to adult, and our tissues grow, mature, and adapt to the postnatal environment. These other, non-ATP-related functions are intimately involved with most of the major metabolic pathways used by a cell to build, break down, and recycle its molecular building blocks. Cells cannot even make the RNA and DNA they need to grow and function without mitochondria. The building blocks of RNA and DNA are purines and pyrimidines. Mitochondria contain the rate-limiting enzymes for pyrimidine biosynthesis (dihydroorotate dehydrogenase) and heme synthesis (d-amino levulinic acid synthetase) required to make hemoglobin. In the liver, mitochondria are specialized to detoxify ammonia in the urea cycle. Mitochondria are also required for cholesterol metabolism, for estrogen and testosterone synthesis, for neurotransmitter metabolism, and for free radical production and detoxification. They do all this in addition to breaking down (oxidizing) the fat, protein, and carbohydrates we eat and drink.



Mitochondrial disorders are the result of either inherited or spontaneous mutations in mtDNA or nDNA which lead to altered functions of the proteins or RNA molecules that normally reside in mitochondria. Problems with mitochondrial function, however, may only affect certain tissues as a result of factors occurring during development and growth that we do not yet understand. Even when tissue-specific isoforms of mitochondrial proteins are considered, it is difficult to explain the variable patterns of affected organ systems in the mitochondrial disease syndromes seen clinically.


Because mitochondria perform so many different functions in different tissues, there are literally hundreds of different mitochondrial disorders. Each disorder produces a spectrum of abnormalities that can be confusing to both patients and physicians in early stages of diagnosis. Because of the complex interplay between the hundreds of genes and cells that must cooperate to keep our metabolic machinery running smoothly, it is a hallmark of mitochondrial diseases that identical mtDNA mutations may not produce identical diseases. Genocopies are diseases that are caused by the same mutation but which may not look the same clinically.

The converse is also true: different mutations in mtDNA and nDNA can lead to the same diseases. In genetics, these are known as phenocopies. A good example is Leigh syndrome, which can be caused by about a dozen different gene defects. Leigh syndrome, originally a neuropathological description of the brain of one affected child, was described by Denis Leigh, the distinguished British physician, in 1951. It is characterized by bilaterally symmetrical MRI abnormalities in the brain stem, cerebellum, and basal ganglia, and often accompanied by elevated lactic acid levels in the blood or cerebrospinal fluid. Leigh syndrome may be caused by the NARP mutation, the MERRF mutation, complex I deficiency, cytochrome oxidase (COX) deficiency, pyruvate dehydrogenase (PDH) deficiency, and other unmapped DNA changes. Not all patients with these DNA abnormalities will go on to develop Leigh syndrome, however.

Mitochondrial diseases are even more complex in adults because detectable changes in mtDNA occur as we age and, conversely, the aging process itself may result from deteriorating mitochondrial function. There is a broad spectrum of metabolic, inherited and acquired disorders in adults in which abnormal mitochondrial function has been postulated or demonstrated.