Mitochondrial disease

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 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 necrotizing encephalomyelopathy
  • 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
• MERRF syndrome
  • progressive myoclonic epilepsy
  • "Ragged Red Fibers" are clumps of diseased mitochondria that accumulate in the subsarcolemmal region of the muscle fiber and appear when muscle is stained with modified Gömöri trichrome stain
  • short stature
  • hearing loss
  • lactic acidosis
  • exercise intolerance
• MELAS syndrome
• Mitochondrial DNA depletion syndrome

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

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.[11] Oxalate may enter cells where it is known to cause mitochondrial dysfunction.[12]

Example of a pedigree for a genetic trait inherited by mitochondrial DNA in animals and humans. Offspring of the males with the trait don't inherit the trait. Offspring of the females with the trait always inherit the trait (independently from their own gender).

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 inherited from the mother only (with some exceptions) and each mitochondrion typically contains between 2 and 10 mtDNA copies. During cell division the mitochondria segregate randomly between the two new cells. Those mitochondria make more copies, normally reaching 500 mitochondria per cell. As mtDNA is copied when mitochondria proliferate, they can accumulate random mutations, a phenomenon called heteroplasmy. 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".

Mitochondria possess many of the same DNA repair pathways as nuclei do—but not all of them;[13] therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA (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 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.[14]

A study by Yale University researchers (published in the February 12, 2004, issue of the New England Journal of Medicine) explored the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes.[15] 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, Louisiana[16] showed that this, in turn, partially disables the genes that produce mitochondria.

The effective overall energy unit for the available body energy is referred to as the daily glycogen generation capacity,[17][18][19] and is used to compare the mitochondrial output of affected or chronically glycogen-depleted individuals to healthy individuals. This value is slow to change in a given individual, as it takes between 18 and 24 months to complete a full cycle.[18]

The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the mitochondria in all of the cells of the human body;[20] however, the relation between the energy generated by the mitochondria and the glycogen capacity is very loose and is mediated by many biochemical pathways.[17] The energy output of full healthy mitochondrial function can be predicted exactly by a complicated theoretical argument, but this argument is not straightforward, as most energy is consumed by the brain and is not easily measurable.

Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:

1. Southern blot to detect large deletions or duplications
2. Polymerase chain reaction and specific mutation testing[21]
3. Sequencing

Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.[22] Pyruvate has been proposed in 2007 as a treatment option.[23] N-acetyl cysteine reverses many models of mitochondrial dysfunction.[24] In the case of mood disorders, specifically bipolar disorder, it is hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options.[25]

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.[37] Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.[38]

The first pathogenic mutation in mitochondrial DNA was identified in 1988; from that time to 2016, around 275 other disease-causing mutations were identified.[39]^: 37

Notable people with mitochondrial disease include:

• Mattie Stepanek, a poet, peace advocate, and motivational speaker who had dysautonomic mitochondrial myopathy, and who died at age 13. [40]
• Rocco Baldelli, a coach and former center fielder in Major League Baseball who had to retire from active play at age 29 due to mitochondrial channelopathy.
• Charlie Gard, a British boy who had mitochondrial DNA depletion syndrome; decisions about his care were taken to various law courts.

Wikimedia Commons has media related to Mitochondrial diseases.

• Mitochondrial disease at Curlie
• International Mito Patients (IMP)