Mitochondrial disease


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, and convert the energy of food molecules into the ATP that powers most cell functions.
Mitochondrial diseases are sometimes (about 15% of the time) caused by mutations in the mitochondrial DNA that affect mitochondrial function. Other causes of mitochondrial disease are mutations in genes of the nuclear DNA, whose gene products are imported into the mitochondria (mitochondrial proteins) as well as acquired mitochondrial conditions. 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.

Symptoms - Mitochondrial disease

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 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, 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.

Causes - Mitochondrial disease

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.

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. During cell division the existing mitochondria segregate randomly between the two new cells, and then those mitochondria make more copies. As mtDNA is copied when mitochondria proliferate, they can accumulate random mutations. 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 mtDNA 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.

A study by Yale University researchers published in the Feb 12, 2004 issue of the New England Journal of Medicine explores the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes. Other studies have shown that the mechanism may involve the interruption of the mitochondrial signaling process in body cells (intramyocellular lipids). A study conducted at the 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.

Distinction between primary mitochondrial disease(PMD) and secondry mitochondrial disfunction (SMD):

PMDs can occur due to germline mutations in mitochondrial DNA (mtDNA) and/or nuclear DNA (nDNA) genes encoding ETC proteins. Point mutations can occur in any of the mtDNA's 37 genes encoding 13 proteins, 22 transfer RNAs (tRNA), and 2 ribosomal RNAs which are essential for optimal ETC function [Chinnery, 2000]. Approximately 250-300 genes are estimated to govern ETC from the nucleus [Powell et al., 2015], and about 1,500 nuclear genes in total are believed to involve mitochondrial processes, including non-ETC functions such as fatty acid oxidation and Krebs cycle. The ETC is organized in 5 complexes including complex I (NADH:ubiquinone oxidoreductase), complex II (succinate dehydrogenase), complex III (CoQ-cytochrome c reductase), complex IV (cytochrome c oxidase), and complex V (ATP synthase). For example, mtDNA genes (such as MT-ND1) encode 7 subunits of the complex I, while nDNA genes (such as NDUFS1) encode additional 38 subunits of complex I [Mimaki et al., 2012]. Complex II is encoded entirely by nDNA genes, while complexes III, IV and V, similar to complex I, have contribution from both mtDNA and nDNA.

PMD occurs not only due to defective genes encoding ETC proteins, but also due to germline mutations in other nDNA genes that affect oxphos function by impacting production of the complex machinery needed for the ETC to perform optimally. Some of the examples include POLG encoding mtDNA polymerase gamma, which replicates mtDNA, and C10ORF2 encoding the twinkle protein, which catalyzes mtDNA unwinding. Even though POLG and C10ORF2 do not encode ETC proteins directly, without these genes ETC function is impaired. When they are mutated they can cause PMD. Deletions in mtDNA may be germline (inherited from the mother) or secondary to nDNA mutations (inherited from the mother and/or father) such as POLG gene mutations, which can cause mtDNA deletions or depletion resulting in PMD.


Examples of mitochondrial diseases include:

  • Mitochondrial myopathy
  • Diabetes mellitus and deafness (DAD)
    • this combination at an early age can be due to mitochondrial disease
    • Diabetes mellitus and deafness can also be found together for other reasons
  • Leber's hereditary optic neuropathy (LHON)
    • visual loss beginning in young adulthood
    • eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina
    • affects 1 in 50,000 people in Finland
  • Leigh syndrome, subacute sclerosing encephalopathy
    • after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood
    • a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
  • Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)
    • progressive symptoms as described in the acronym
    • dementia
  • Myoneurogenic gastrointestinal encephalopathy (MNGIE)
    • gastrointestinal pseudo-obstruction
    • neuropathy
  • Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
    • progressive myoclonic epilepsy
    • "Ragged Red Fibers" – clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain
    • short stature
    • hearing loss
    • lactic acidosis
    • exercise intolerance
  • Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)
  • mtDNA depletion
    • mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Prevention - Mitochondrial disease

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Diagnosis - Mitochondrial disease

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Prognosis - Mitochondrial disease

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Treatment - Mitochondrial disease

Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited. Membrane penetrating antioxidants, such as the mitochondria-targeted antioxidant MitoQ (mitoquinol mesylate) have the most important role in improving mitochondrial dysfunction. Pyruvate has been proposed recently as a treatment option. N acetylcysteine reverses many models of mitochondrial dysfunction.

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. Using a similar pronuclear transfer technique, researchers at Newcastle University led by Douglass Turnbull successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. In such cases, ethical questions have been raised regarding biological motherhood, since the child receives genes and gene regulatory molecules from two different women. Using genetic engineering in attempts to produce babies free of mitochondrial disease is controversial in some circles and raises important ethical issues.

In September 2012 a public consultation was launched in the UK to explore the ethical issues involved. Human genetic engineering was used on a small scale to allow infertile women with genetic defects in their mitochondria to have children. In June 2013, the United Kingdom government agreed to develop legislation that would 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 from 29 October 2015 once regulations had been established. 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.

Resources - Mitochondrial disease

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by Scott Harwood
Research Publications