Mitochondrial disease
Encyclopedia
Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelle
s that are the "powerhouses" of 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 often caused by genetics or mutations to the mitochondrial DNA
that affect mitochondria 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
.
There is some evidence for mitochondrial dysfunction as the molecular basis of bipolar disorder. In addition, classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits.
Nota bene: Conditions such as Friedreich's ataxia
can affect the mitochondria, but are not associated with mitochondrial proteins.
", 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 muscle
s, cerebrum, or nerve
s, 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.
, infections, or other environmental causes (see MeSH
).
Mitochondrial DNA inheritance behaves differently from autosomal and sexually-linked inheritance. 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
.
s are frequently prescribed, though the evidence for their effectiveness is limited. Membrane penetrating antioxidants have the most important role in improving mitochondrial dysfunction.
Pyruvate has been proposed recently as a treatment option.
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 successfully transplanted healthy DNA in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected.
Human genetic engineering is already being used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.
Embryo
nic 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.
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.
"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 Cernter in Baton Brouge, LA (Diabetes 54, 2005 1926-33) showed that this in turn partially disables the genes that produce mitochondria.
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s that are the "powerhouses" of 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
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
that powers most cell functions.
Mitochondrial diseases are often caused by genetics or mutations to the mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
that affect mitochondria 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
Mitochondrial myopathy
Mitochondrial myopathy is a type of myopathy associated with mitochondrial disease. On biopsy, the muscle tissue of patients with this disease usually demonstrate "ragged red" muscle fibers...
.
There is some evidence for mitochondrial dysfunction as the molecular basis of bipolar disorder. In addition, classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits.
Classification
In addition to the mitochondrial myopathies, other examples include:- Diabetes mellitus and deafnessDiabetes mellitus and deafnessDiabetes mellitus and deafness or maternally inherited diabetes and deafness is a mitochondrial disease associated with the gene "Leu-UUR".-Alternative names:*diabetes and deafness, maternally inherited; MIDD*Ballinger-Wallace syndrome...
(DAD)- this combination at an early age can be due to mitochondrial disease
- Diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and deafness can also be found together for other reasons
- Leber's hereditary optic neuropathyLeber's hereditary optic neuropathyLeber’s hereditary optic neuropathy or Leber optic atrophy is a mitochondrially inherited degeneration of retinal ganglion cells and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males...
(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
- Wolff-Parkinson-White syndromeWolff-Parkinson-White syndromeWolff–Parkinson–White syndrome is a disorder of the heart in which the ventricles of the heart contract prematurely due to an accessory pathway known as the bundle of Kent. This accessory pathway is an abnormal electrical communication from the atria to the ventricles...
- multiple sclerosisMultiple sclerosisMultiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
-type disease - 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 (NARPNeuropathy, ataxia, and retinitis pigmentosaNeuropathy, ataxia, and retinitis pigmentosa is a condition that causes a variety of signs and symptoms chiefly affecting the nervous system. Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs ; muscle weakness; and problems...
)- progressive symptoms as described in the acronym
- dementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
- Myoneurogenic gastrointestinal encephalopathyMyoneurogenic gastrointestinal encephalopathyMitochondrial neurogastrointestinal encephalopathy syndrome , also called myoneurogastrointestinal encephalopathy syndrome or POLIP syndrome, is a rare autosomal recessive mitochondrial disease usually appearing between the second and fifth decades of life...
(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 subsarcolemmaSarcolemmaThe sarcolemma is the cell membrane of a muscle cell . It consists of a true cell membrane, called the plasma membrane, and an outer coat made up of a thin layer of polysaccharide material that contains numerous thin collagen fibrils...
l region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stainGomori trichrome stainGömöri trichrome stain is a stain used on muscle tissue.It can be used to test for certain forms of mitochondrial myopathy.It is named for George Gömöri, who developed it in 1950.-External links:... - short stature
- hearing loss
- lactic acidosis
- exercise intolerance
- Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptomsMELASMitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes – abbreviated to MELAS – is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984...
(MELAS) - mtDNA depletion
- mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
Nota bene: Conditions such as Friedreich's ataxia
Friedreich's ataxia
Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease and diabetes....
can affect the mitochondria, but are not associated with mitochondrial proteins.
Symptoms
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.Characteristics
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 intoleranceExercise intolerance
Exercise intolerance is a condition where the patient is unable to do physical exercise at the level or for the duration that would be expected of someone in his or her general physical condition, or experiences unusually severe post-exercise pain, fatigue, or other negative effects...
", 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 muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s, cerebrum, or nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s, 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 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 drugsDRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
, infections, or other environmental causes (see MeSH
Medical Subject Headings
Medical Subject Headings is a comprehensive controlled vocabulary for the purpose of indexing journal articles and books in the life sciences; it can also serve as a thesaurus that facilitates searching...
).
Mitochondrial DNA inheritance behaves differently from autosomal and sexually-linked inheritance. Nuclear DNA
Nuclear DNA
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
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
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
typically contains multiple mtDNA copies (see Heteroplasmy
Heteroplasmy
Heteroplasmy is the presence of a mixture of more than one type of an organellar genome within a cell or individual...
). During cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
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
Human mitochondrial genetics
Human mitochondrial genetics is the study of the genetics of the DNA contained in human mitochondria. Mitochondria are small structures in cells that generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell....
). Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression
Threshold expression
Threshold expression is a phenomenon in which phenotypic expression of a mitochondrial disease within an organ system occurs when the severity of the mutation, relative number of mutant mtDNA, and reliance of the organ system on oxidative phosphorylation combine in such a way that ATP production of...
".
Mitochondrial DNA mutations occur frequently, due to the lack of the error checking capability that nuclear DNA has (see Mutation rate
Mutation rate
In genetics, the mutation rate is the chance of a mutation occurring in an organism or gene in each generation...
). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
(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
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
. 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
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, retinopathy
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
, seizures, and neurodevelopmental disorders
Neurodevelopmental Disorders
A neurodevelopmental disorder, or disorder of neural development, is an impairment of the growth and development of the brain or central nervous system. A narrower use of the term refers to a disorder of brain function that affects emotion, learning ability and memory and that unfolds as the...
.
Treatment
Although research is ongoing, treatment options are currently limited; vitaminVitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s are frequently prescribed, though the evidence for their effectiveness is limited. Membrane penetrating antioxidants have the most important role in improving mitochondrial dysfunction.
Pyruvate has been proposed recently as a treatment option.
Spindle transfer
Spindle transfer
A spindle transfer is a genetic manipulation technique where the donor's mitochondrial DNA is not transferred to the receiving egg. It may be used to treat mitochondrial diseases.-History:...
, where the nuclear DNA
Nuclear DNA
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
is transferred to another healthy egg cell leaving the defective mitochondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
behind, is a potential treatment procedure that has been successfully carried out on monkeys.
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.
Human genetic engineering is already being used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.
Embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic mitochondrial transplant and protofection
Protofection
Protofection is a term that refers to the transfection of foreign mitochondrial DNA to replace the original energy generators within cells. As mitochondria are damaged with age, this would be a method of rejuvenating them to original states....
have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression
Allotopic expression
Allotopic expression refers to expression from the nuclear genome of genes that normally are expressed only from the mitochondrial genome. Biomedically engineered AE has been suggested as a possible future tool in gene therapy of certain mitochondria-related diseases , however this view is...
of mitochondrial proteins as a radical treatment for mtDNA mutation load.
Statistics
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.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.
"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 Cernter in Baton Brouge, LA (Diabetes 54, 2005 1926-33) showed that this in turn partially disables the genes that produce mitochondria.
People
Notable people who suffered from mitochondrial disease include:- Rocco BaldelliRocco BaldelliRocco Dan Baldelli is a former Major League Baseball outfielder and designated hitter. Because of his excellent size and speed, and in reference to his hometown, he was nicknamed, "The Woonsocket Rocket," early in his professional career...
(diagnosis later replaced by channelopathy) - Mattie StepanekMattie StepanekMatthew Joseph Thaddeus Stepanek , known as Mattie Stepanek, was an American poet, who had six books of poetry and one book of essays all reach The New York Times bestsellers list...
(dysautonomic mitochondrial myopathy) - Colby Wren