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.

Alpers Disease
Barth syndrome
Beta-oxidation Defects
Carnitine-Acyl-Carnitine Deficiency
Carnitine Deficiency
Creatine Deficiency Syndromes
Co-Enzyme Q10 Deficiency
Complex I Deficiency
Complex II Deficiency
Complex III Deficiency
Complex IV Deficiency
Complex V Deficiency
COX Deficiency
CPT I Deficiency
CPT II Deficiency
Glutaric Aciduria Type II
Kearns Sayre Syndrome
Lactic Acidosis
Leigh Disease or Syndrome - Connect with other Leigh patients

LIC (Lethal Infantile Cardiomyopathy)
Luft Disease
Mitochondrial Carrier Related Diseases
Mitochondrial Cytopathy
Mitochondrial DNA Depletion
Mitochondrial Encephalopathy
Mitochondrial Myopathy
Pearson Syndrome
Pyruvate Carboxylase Deficiency
Pyruvate Dehydrogenase Deficiency
POLG Mutations
Respiratory Chain

For those who wish to read about the details of the different disorders: the OMIM catalogue of human genes and genetic disorders

Sources include publications by Drs. Salvatore DiMauro (Metabolic Myopathies; Handbook of Clinical Neurology; 1992; 18(62); 479-522) and Richard Haas (Disorders of Oxidative Metabolism and Mitochdondria; Neurology in Clinical Practice, Bradley, et al, Chapt 69; 1996; 1523-32).


Developmental delays
Neuro-psychiatric disturbances
Autistic Features
Mental retardation
Atypical cerebral palsy
Strokes/Stroke-like episodes

Weakness (may be intermittent)
Absent reflexes
Neuropathic pain
Dysautonomia - temperature instability
other dysautonomic problems

Dysphagia (swallowing problems)
Gastrointestinal problems
Irritable bowl syndrome
Muscle pain
Gastroesophogeal reflux
Diarrhoea or constipation

Renal tubular acidosis or wasting

Cardiac conduction defects (heart blocks)

Hypoglycemia (low blood sugar)
Liver failure

Hearing loss and deafness
Visual loss and blindness
Optic atrophy
Acquired strabismus
Retinitis pigmentosa

Diabetes and exocrine pancreatic failure
(inability to make digestive enzymes)
Parathyroid failure (low calcium)

Failure to gain weight
Unexplained vomiting
Short stature
Respiratory problems

On the basis of the first symptoms people usually go to their general physician. Mostly these first symptoms will be weakness of the muscles or unexplained fatigue. In many cases the general physician will try to find out the cause of these complaints. With respect to mitochondrial disease this will turn out to be a difficult road. A referral to a specialist (neurologist, paediatrician or internist/internal specialist) will be the next step. It is to be advised that the referral involves an appropriate expertise or research centre with a specific metabolic research laboratory.

When the symptoms point towards a suspicion of mitochondrial disease, different ways exist to establish the disease. In all cases the level of lactate in the blood and also in the brain liquids will be determined. The last is done by means of an epidural. Additionally, in most cases a urine sample is tested for lactate and other substances. Another kind of screening test is the exercise test with a home trainer or a treadmill, where the level of oxygen uptake is measured. By comparing these measurements with standards this will result in an indication into the cause of the disease.

In cases of mental retardation or development issues a brain scan is done, usually a MRI scan. With DNA tests established and occurring mutations can be determined. Additionally, research into certain symptoms in the family (deafness, migraines, short stature) can be useful for a final diagnosis. For a final and complete diagnosis a biopsy of a small piece of muscle is required, with the purpose of testing it for mutated mitochondria. Such a biopsy can only be executed by qualified medical centres. Despite these methods many cases do not receive a specific diagnosis.

Mitochondrial disease is very difficult to diagnose and requires specialist knowledge. Therefore, it is essential for patients to find the appropriate research centre, which sometimes is not a simple task to do. Not all general physicians or clinicians are familiar with mitochondrial disease and know the way towards the right research centre. In addition, a single blood or urine lab test with normal results does not rule out a mitochondrial disease. This is true for organic acids, lactic acid, carnitine analysis and amino acid analysis. Even muscle biopsies are not 100% accurate.

If you wish to find the appropriate centre for diagnosis of mitochondrial disease, please contact your national patient organisation or contact IMP.



Scientific research into mitochondrial disease is done on a worldwide scale. The scientists and clinicians involved have ongoing communication with each other. Active networks exist of university research centres, laboratories, patient organisations etc. Research is costly and time-consuming. The majority of the mitochondrial studies is carried out internationally and is financed by national and European funds. The application for grants is almost a fulltime job for some researchers, but is an essential part of the work. IMP will support these applications whenever possible.

Research into mitochondrial disease covers many different fields and subjects. It varies from research into gene-defects, diagnostic methods, DNA structures, the addition of enzyme compounds, to the scientific studies into the inheritance of the disease. National patient organisations inform their members about any new development in this field. Naturally, IMP will be on the forefront of what is happening here.


Mitochondrial dysfunction is at the core of a surprising range of very common illnesses and conditions, and a promising new avenue for their treatment. As the mitochondria are responsible for producing energy, any illness that has an energy problem could be related to the mitochondria.

Diseases in which mitochondrial dysfunction have been implicated include:

  1. Alzheimer's Dementia, Parkinson's disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), mental retardation, deafness and blindness, diabetes, obesity, cardiovascular disease and stroke.
  2. Even autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus and rheumatoid arthritis appear to have a mitochondrial basis to illness. 


Mitochondrial dysfunction has been associated with a wide range of solid tumours, proposed to be central to the aging process, and found to be a common factor in the toxicity of a variety of physical and chemical agents. Until recently, the broad range of diseases that may be caused by mitochondrial dysfunction was not well understood or appreciated. A relationship between mitochondrial dysfunction and a wide range of disease states was known to exist, but whether mitochondrial dysfunction was responsible for the particular disease was still in question. This changed with the discovery that mutations of the mitochondrial DNA could cause certain diseases. For the first time, scientists showed that a single nucleotide change in mitochondrial DNA of a mouse led to the development of muscle weakness and progressive heart disease.


Research supporting the link between mitochondrial dysfunction and some of these other common illnesses includes:

  1. Mitochondrial coenzyme Q10 levels are reduced in patients with Parkinson's disease and mitochondrial function in these patients is impaired.
  2. Results of the first placebo-controlled clinical trial of the compound coenzyme Q10 suggest that it can slow down progression in patients with early-stage Parkinson's disease.
  3. These findings are consistent with another recent study involving patients with early onset Huntington's disease. These patients showed slightly less functional decline in groups receiving coQ10. Investigators believe coQ10 works by improving the function of the mitochondria.
  4. A drug once approved as an antihistamine in Russia improved thinking processes and the ability to function in Alzheimer's disease patients. The drug works by stabilizing mitochondria.
  5. Cancers are also associated with defects in the mitochondria. Within the cell, signaling must occur between the mitochondria and the nucleus. When the signaling malfunctions, the defect can cause cancer.
  6. Researchers discovered that mutations in the mitochondrial DNA may play a role in tumor metastasis and suggests a possible new avenue for the development of a treatment to suppress metastasis.
  7. Researchers have found a very consistent decline in mitochondrial function that is found in diabetes and and pre-diabetes.
  8. There is increasing interest in the possibility that mitochondrial dysfunction might play an important role in the etiology of autism. A subset of autistic children have already been shown to manifest biochemical alterations that are commonly associated with mitochondrial disorders, and a few have been linked to specific alterations in the mitochondrial genes.

It is clear that research into mitochondrial disease offers hope to the millions who are afflicted with these other common conditions and diseases.

In general, mitochondrial disease is a progressive disorder. A substantial number of children with mitochondrial disease die before the age of 10 years. The disease can affect patients severely, but there are also mild variations. The rate of decline is unpredictable and very long stable periods may occur.

Most patients eventually develop involvement of several organ systems. Since mitochondrial disease involves a very heterogeneous group of patients, no general statements about the prognosis of these patients can be made. Prognosis is dependent mainly on which and how severely organs are affected, and on the progression rate, which is very individual.


The degree in which a patient with mitochondrial disease is ill depends on the production of energy. An infection or another external factor may have a negative impact on the energy levels and as a result may deteriorate the situation of a mitochondrial patient for a longer period. An innocent attack of the flu may cost so much energy that it takes a long time before the patient is back at his/her earlier level of health. Sometimes this level is never recaptured again.

There is no obvious relationship between the age of onset of the disease and the level of severity of the disease. Unfortunately, children with a progressive and serious mitochondrial disease often die at an early age. It happens, but only rarely so, that the clinical situation of a patient improves over time.

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