Mitochondrial DNA disease is a group of disorders caused by mitochondrial dysfunction.
Mitochondria are cell organelles that generate energy for the cell and are found in every cell of the human body except red blood cells.
They convert the energy of food molecules into the ATP that powers most cell functions.
mtDNA is a circular DNA in the mitochondria that includes 22 transfer RNAs, two ribosomal RNAs, and 13 protein subunits involved in the oxidative phosphorylation pathway.
Mitochondria is composed of proteins encoded by these genes, together with protein encoded by nuclear genes.
In many patients with mitochondrial disease mtDNA with a pathogenic mtDNA variant coexists with mtDNA without the variant.
Clinical symptoms depend on the extent of heteroplasmy in vulnerable tissues.
In some patients with mitochondrial disease, 100% of their mtDNA carries the pathologic variant.
A subclass of these diseases that have neuromuscular symptoms are known as mitochondrial myopathies.
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.
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.
Mitochondrial disease can manifest in many different ways in children or adults.
Pathogenic damaging variants in mtDNA are responsible for severe maternally inherited disorders with a high risk of transmission, including mitochondrial and encephalopathy with lactic acidosis and stroke like episodes (MELAS) syndrome.
Mitochondrial diseases include:
Mitochondrial myopathy
Maternally inherited diabetes mellitus and deafness (MIDD), as may occur in Kearns–Sayre syndrome and Pearson syndrome Leber’s hereditary optic neuropathy (LHON), an eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina with visual loss typically begins in young adulthood.
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-clumps of diseased mitochondria that accumulate in the subsarcolemmal region of the muscle fiber and appear when muscle is stained with modified short stature hearing loss lactic acidosis exercise intolerance
MELAS syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
Mitochondrial DNA depletion syndrome.
Mitochondrial maintenance remains crucial for tumor resilience, redox regulation, and avoidance of cell death.
The onset and severity of symptoms in mtDNA diseases depend on the level of heteroplasmy, with clinical manifesting once the various specific threshold is exceeded.
Higher levels of heteroplasmy in women increase the risk of transmitting mtDNA disease to their offspring.
Tumor cells exhibit metabolic heterogeneity, shifting between glycolysis and mitochondrial oxidative phosphorylation to meet energy demands and support growth, especially during metastasis.
Acquired conditions in which mitochondrial dysfunction has been involved include:
ALS Alzheimer’s disease Bipolar disorder, schizophrenia, aging and senescence, anxiety disorders Cancer Cardiovascular disease Diabetes Huntington’s disease Long Covid ME/CFS/chronic fatigue syndrome Parkinson’s disease Sarcopenia
Some gene mutation defects include exercise intolerance.
Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.
It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria, which suggested an increase in mitochondrial biogenesis.
Cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.
Mitochondrial diseases 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.
Mitochondrial disorders may be caused by mutations either acquired or inherited, in mitochondrial DNA (mtDNA), or in nuclear genes that code for mitochondrial components.
Mitochondrial disorders may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes.
Offspring of the males with the trait don’t inherit the trait.
Offspring of the females with the trait always inherit the trait.
Nuclear DNA has two copies per cell, except for sperm and egg cells, with one copy being inherited from the father and the other from the mother.
Mitochondrial DNA, however, is inherited from the mother only and each mitochondrion typically contains between 2 and 10 mtDNA copies.
Children receive their mitochondrial DNA (mtDNA) from their mother, and this mtDNA is nearly identical to the mother’s, barring new mutations.
Both sons and daughters inherit maternal mtDNA, but only daughters can pass it on to the next generation
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, known as heteroplasmy.
Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; referred to as a “threshold expression”.
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 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.
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: anemia, dementia, hypertension, lymphoma, retinopathy, seizures, and neurodevelopmental disorders.
The glycogen generation capacity refers to the maximum amount of carbohydrates the body can store as glycogen and the rate at which it can replenish those stores.
The capacity is limited and primarily stored in the skeletal muscles and the liver.
The effective overall energy unit for the available body energy is referred to as the daily glycogen generation capacity.
Glycogen generation capacity is used to compare the mitochondrial output of affected or chronically glycogen-depleted individuals to healthy individuals.
The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the mitochondria in all of the cells of the body;
The relation between the energy generated by the mitochondria and the glycogen capacity is loose and is mediated by many biochemical pathways.
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:
Southern blot to detect large deletions or duplications Polymerase chain reaction and specific mutation testing Sequencing
Treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.
Treatment of mitochondrial diseases encompasses both established supportive care approaches and emerging innovative therapies.
Most patients receive primarily supportive and symptomatic treatments.
Most experts use a combination of vitamins, optimize patients’ nutrition and general health, and prevent worsening of symptoms during times of illness and physiologic stress.
Treatment typically includes vitamin supplementation, nutritional optimization, and metabolic support to help compensate for impaired cellular energy production.
This may involve supplements like coenzyme Q10, creatine, and various B vitamins.
While traditional vitamin supplementation and symptom management remain important, gene therapy, precision medicine, and novel therapeutic mechanisms offer hope for more effective treatments.
Prenatal diagnosis/pre-implantation genetic testing rely on quantifying the variant mtDNA load analysis of the amniotic fluid in the prenatal diagnosis.