Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction.
Mitochondria are the
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.
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. A subclass of these diseases that have
neuromuscular symptoms are known as
mitochondrial myopathies
Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulation ...
.
Types
Examples of mitochondrial diseases include:
*
Mitochondrial myopathy
Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulati ...
*
Diabetes mellitus and deafness
Diabetes and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or mitochondrial diabetes is a subtype of diabetes which is caused from a point mutation at position 3243 in human mitochondrial DNA, which consists of a circular g ...
(DAD)
** this combination at an early age can be due to mitochondrial disease
**
Diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
and
deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...
can be found together for other reasons
*
Leber's hereditary optic neuropathy
Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...
(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
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fi ...
, 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
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
*
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
** gastrointestinal pseudo-obstruction
**
neuropathy
*
MERRF syndrome
MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the ...
** progressive myoclonic epilepsy
** "Ragged Red Fibers" are clumps of diseased mitochondria that accumulate in the sub
sarcolemma
The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte.
It consists of a lipid bilayer and a thin oute ...
l region of the muscle fiber and appear when muscle is stained with modified
Gömöri trichrome stain
Gömöri trichrome stain is a histological stain used on muscle tissue.
It can be used to test for certain forms of mitochondrial myopathy.
It is named for George Gömöri George Gomori may refer to:
* György Gömöri (1904–1957), Hungari ...
** short stature
** hearing loss
** lactic acidosis
** exercise intolerance
*
MELAS syndrome
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD (maternally inherited diabetes and deafness, MERRF syndrome, and Leber's hereditary optic neu ...
*
Mitochondrial DNA depletion syndrome
''Conditions such as
Friedreich's ataxia
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 year ...
can affect the
mitochondria but are not associated with mitochondrial proteins.''
Presentation
Associated conditions
Acquired conditions in which mitochondrial dysfunction has been involved are:
*
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
*
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
*
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
*
Alzheimer's disease,
*
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
*
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
,
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
, aging and senescence, anxiety disorders
*
cardiovascular disease
*
sarcopenia
Sarcopenia is a type of muscle loss ( muscle atrophy) that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, ...
*
chronic fatigue syndrome
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 defects include
exercise intolerance
Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...
. 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.
Interestingly, a recent study in ''Nature Nanotechnology'' has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.
As a rule, mitochondrial diseases are worse when the defective mitochondria are present in the
muscles,
cerebrum
The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb ...
, 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.
Cerebellar atrophy or
hypoplasia has sometimes been reported to be associated.
Causes
Mitochondrial disorders may be caused by
mutations (acquired or inherited), in
mitochondrial DNA (mtDNA), or in
nuclear gene
A nuclear gene is a gene whose physical DNA nucleotide sequence is located in the cell nucleus of a eukaryote. The term is used to distinguish nuclear genes from genes found in mitochondria or chloroplasts. The vast majority of genes in eukary ...
s that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of
drugs,
infections
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
, or other environmental causes.
Oxalate
Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl ...
may enter cells where it is known to cause mitochondrial dysfunction.
Nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
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
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DNA ...
copies. During
cell division
Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
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
Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells c ...
. 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
Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA (the DNA contained in human mitochondria). The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondri ...
). 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; therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA (see
Mutation rate
In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates ...
). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
(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
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
. Human mitochondrial DNA encodes 13 proteins of the
respiratory chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples thi ...
, 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
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
,
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
,
hypertension,
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enla ...
,
retinopathy
Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically inc ...
,
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
, and
neurodevelopmental disorders
Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
.
A study by Yale University researchers (published in the February 12, 2004, issue of the ''
New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one.
His ...
'') explored 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, Louisiana showed that this, in turn, partially disables the genes that produce mitochondria.
Mechanisms
The effective overall energy unit for the available body energy is referred to as the daily
glycogen generation capacity,
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.
[
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;] however, the relation between the energy
In physics, energy (from Ancient Greek: ἐνέργεια, ''enérgeia'', “activity”) is the quantitative property that is transferred to a body or to a physical system, recognizable in the performance of work and in the form of hea ...
generated by the mitochondria and the glycogen capacity is very loose and is mediated by many biochemical pathways
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
. 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.
Diagnosis
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
The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
and specific mutation testing
Mutation testing (or ''mutation analysis'' or ''program mutation'') is used to design new software tests and evaluate the quality of existing software tests. Mutation testing involves modifying a program in small ways. Each mutated version is call ...
# Sequencing
Treatments
Although research is ongoing, treatment options are currently limited; vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
s are frequently prescribed, though the evidence for their effectiveness is limited.
Pyruvate has been proposed in 2007 as a treatment option. N-acetyl cysteine reverses many models of mitochondrial dysfunction. In the case of mood disorders, specifically bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, 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.
Gene therapy prior to conception
Mitochondrial replacement therapy
Mitochondrial replacement therapy (MRT), sometimes called mitochondrial donation, is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some o ...
(MRT), where the nuclear DNA
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind, is an IVF
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
treatment procedure. 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
Ethics or moral philosophy is a branch of philosophy that "involves systematizing, defending, and recommending concepts of right and wrong behavior".''Internet Encyclopedia of Philosophy'' The field of ethics, along with aesthetics, concerns ma ...
. A male baby was born in Mexico in 2016 from a mother with Leigh syndrome using MRT.
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
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...
government agreed to develop legislation that would legalize the 'three-person IVF
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
' 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.[The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 No. 572]
/ref>
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.
In June 2018 Australian Senate's Senate Community Affairs References Committee recommended a move towards legalising Mitochondrial replacement therapy
Mitochondrial replacement therapy (MRT), sometimes called mitochondrial donation, is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some o ...
(MRT). Research and clinical applications of MRT were overseen by laws made by federal and state governments. State laws were, for the most part, consistent with federal law. In all states, legislation prohibited the use of MRT techniques in the clinic, and except for Western Australia, research on a limited range of MRT was permissible up to day 14 of embryo development, subject to a license being granted. In 2010, the Hon. Mark Butler MP, then Federal Minister for Mental Health and Ageing, had appointed an independent committee to review the two relevant acts: the ''Prohibition of Human Cloning for Reproduction Act 2002'' and the ''Research Involving Human Embryos Act 2002''. The committee's report, released in July 2011, recommended the existing legislation remain unchanged
Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.
Epidemiology
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
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...
and 800 in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
.
History
The first pathogenic mutation in mitochondrial DNA was identified in 1988; from that time to 2016, around 275 other disease-causing mutations were identified.[Index page]
with links to summaries includin
one page summary flyer
Notable cases
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.
* Rocco Baldelli
Rocco Daniel Baldelli (; born September 25, 1981) is an American former professional baseball outfielder and coach who is the manager of the Minnesota Twins of Major League Baseball (MLB). As a player, Baldelli quickly progressed through the min ...
, a coach and former center fielder in Major League Baseball
Major League Baseball (MLB) is a professional baseball organization and the oldest major professional sports league in the world. MLB is composed of 30 total teams, divided equally between the National League (NL) and the American League (AL), ...
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.
References
External links
* {{Curlie, Health/Conditions_and_Diseases/Neurological_Disorders/Brain_Diseases/Metabolic/Mitochondrial/
International Mito Patients (IMP)
Molecular biology
Mitochondrial genetics