Mitochondrial diseases

Mitochondrial disease
Classification and external resources
9 DiseasesDB MeSH D028361

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Mitochondria are found in every cell of the human body except red blood cells. Mitochondria convert the energy of food molecules into the ATP that powers most cell functions.

Mitochondrial diseases are sometimes (about 15% of the time)[1] caused by the mitochondrial DNA that affect mitochondrial function. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often called a mitochondrial myopathy.


In addition to the mitochondrial myopathies, other examples include:

Nota bene: Conditions such as Friedreich's ataxia can affect the mitochondria, but are not associated with mitochondrial proteins.


Symptoms include poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction and dementia.


The effects of mitochondrial disease can be quite varied. Since the distribution of the defective mitochondrial DNA may vary from organ to organ within the body, and each mutation is modulated by other genome variants, the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.

Mitochondrial diseases as a rule are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves,[2] because these cells use more energy than most other cells in the body.

Although mitochondrial diseases vary greatly in presentation from person to person, several major clinical categories of these conditions have been defined, based on the most common phenotypic features, symptoms, and signs associated with the particular mutations that tend to cause them.

An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.

Energetics of mitochondrial deactivation

The effective overall energy unit for the available body energy is the daily glycogen generation capacity.[3][4][5] It has to be considered against what levels are supposed to be there in healthy individuals, compared with what levels actually is there in the chronically glycogen-depleted individual. It takes a very long time to alter the glycogen generation capacity. It completes a full cycle, after 18–24 months.[4] This is equal in length to the maximum training cycle for athletic performance or the recovery cycle after a complete and serious injury, like multiple fractures of one or several bones. The glycogen generation capacity is entirely dependent on, and determined by, the correct operation by healthy and functioning mitochondria in all of the cells of the human body.[6] The relation between the energy generated by the mitochondria and the glycogen capacity generation is abstract and is mediated by the available biochemical pathways.[3] The energy output of full healthy mitochondrial function can be determined exactly by a complicated theoretical argument ( this argument is not straightforward, as most energy is used up in the brain and this effect is not easily measurable, meaning muscle power performance or is not a reliable measure of the available body energy, though they often give an indication of glycogen capacity damage, though simpler arguments describing the same phenomen follows in next sentence.) Inactivated mitochondria is just another term for the cellular reaction called glycolosis,[4] an intermediate reaction present in all cells. This reaction has been studied extensively,[7][8] and shown to output between 6 and 8 ATP out of 38 ATP theoretically possible,[8] thereby generating only around 16-21% of normal cellular energy generation,[9] where the remaining approximately 80% of the rest of the cellular energy normally required, requires an constant oxygen utilization for this complete reaction to occur, though oxygen is known to be present under all conditions, but not utilized under glycolytic circumstances.[9] The exact theoretical result of inactivated mitochondria is a 81% loss of daily available body energy.[9] This 81% daily energy loss factor has to be multiplied with the 18-24 month damage cycle factor, in order to understand the damage of total mitochondrial deactivation on the body over time.[10] This means the body will lose 81% of the available daily energy by mitochondrial obstruction, yet an 81% overall loss of available body energy in the form of glycogen capacity compared to the individual`s healthy maximum potential, does not happen until all the mitochondria has been obstructed daily for a continuous period of 18–24 months, after which a minimum glycogen capacity is reached which does not sink much further. In this case the affected body is in an overall glycolytic state with no real glycogen generation.[3] The most common and severe cause of mitochondrial deactivation with a resulting 81% available body energy loss is the class of pharmaceutical drugs called neuroleptics or antipsychotics, widely used in mental health treatment.[10] Other causes of mitochondrial deactivation, not caused directly by other humans, is cancer tumours,[4] which causes local tissue-specific mitochondrial deactivation, but not full body mitochondrial deactivation like the pharmaceutical drugs known as neuroleptics or antipsychotics do.[10] Also diabetes and other metabolic complications are thought to be a symptom of not optimally functioning mitochondria. Reactivating mitochondria requires the continuous 18-24 month removal of mitochondria-obstructing drugs like is the case in the case of mitochondrial destruction caused by neuroleptics or antipsychotics.[10] Cancer is a biological condition where the cause of mitochondrial inactivation is unknown and cannot be identified, therefore removal of a theorized cause does not necessarily work, and last resort may very well be the use of the artificial temporarily mitochondrial reactivating substance called sodium dichloroacetate,[6][11] although a variety of surgical and metabolical altering alternatives exist, each with different modes of operation and different degrees of success. For diabetes a wide variety of metabolic stimulators are available, including sodium dichloroacetate.[5]


Mitochondrial disorders may be caused by mutations, acquired or inherited, in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes (see MeSH).

Nuclear DNA has two copies per cell (except for sperm and egg cells), one copy being inherited from the father and the other from the mother. Mitochondrial DNA, however, is strictly inherited from the mother and each mitochondrial organelle typically contains multiple mtDNA copies (see Heteroplasmy). During cell division the mitochondrial DNA copies segregate randomly between the two new mitochondria, and then those new mitochondria make more copies. If only a few of the mtDNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria (for more detailed inheritance patterns, see Human mitochondrial genetics). Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression".

Mitochondrial DNA mutations occur frequently, due to the lack of the error checking capability that nuclear DNA has (see Mutation rate). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial DNA replication (all of which are encoded for by genes in the nuclear DNA) may also cause mitochondrial DNA mutations.

Most mitochondrial function and biogenesis is controlled by nuclear DNA. Human mitochondrial DNA encodes only 13 proteins of the respiratory chain, while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and neurodevelopmental disorders.[12]


Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.[13] Membrane penetrating antioxidants have the most important role in improving mitochondrial dysfunction. Pyruvate has been proposed recently as a treatment option.[14]

Spindle transfer, where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is a potential treatment procedure that has been successfully carried out on monkeys.[15] [16] Using a similar pronuclear transfer technique, researchers at Newcastle University successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected.[17] [18] In September 2012 a public consultation was launched in the UK to explore the ethical issues involved.[19] Human genetic engineering is already being used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.[20] On 26 June 2013, the United Kingdom government agreed to legalize the three-person IVF procedure as a treatment to fix or eliminate mitochondrial diseases that are passed on from mother to child. The procedure could be offered within two years once regulations are established.[21]

Embryonic mitochondrial transplant and protofection have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial proteins as a radical treatment for mtDNA mutation load.

These three films produced for the Human Fertilization Authority explain how Mitochondria Replacement treatment works, and what the ethical and practical considerations are:


About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease.[22] Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

Many diseases of aging are caused by defects in mitochondrial function. Since the mitochondria are responsible for processing oxygen and converting substances from the foods we eat into energy for essential cellular functions, if there are problems with the mitochondria, it can lead to many defects for adults. These include Type 2 diabetes, Parkinson's disease, atherosclerotic heart disease, stroke, Alzheimer's disease, and cancer. Many medicines can also injure the mitochondria.[23]

"Inside the Cell" in Dr. Neal Barnard's Program for Reversing Diabetes, Rodale Press, 2007, pp. 22 – 27, which references the Feb 12, 2004 issue of the New England Journal of Medicine, an article by Yale University researchers. Dr. Barnard also references other studies in his explanation of how, in Type 2 diabetes, the mitochondria signaling process is interrupted by fats in body cells (intramyocellular lipids) which have not been properly treated. A study at Pennington Biomedical Research Center in Baton Rouge, LA (Diabetes 54, 2005 1926-33) showed that this in turn partially disables the genes that produce mitochondria.


Notable people who suffered from mitochondrial disease include:


External links

  • - The mitochondrial disease database
  • DMOZ
  • United Mitochondrial Disease Foundation
  • Friedreich's Ataxia Research Alliance (FARA)
  • Mitochondrial Disease Action Committee
  • Foundation for Mitochondrial Medicine

Three films produced by Close-Up Research for the Human Embryology Authority, explaining what mitochondrial disease is, and what the ethical and practical considerations are for Mitochondria Replacement treatment:

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.