INTRODUCTION — Mitochondrial diseases can be defined as a group of chronic, genetically determined disorders caused by dysfunction of the mitochondria, which are organelles found in almost every cell type in the human body. Mitochondrial diseases encompass myopathies, encephalomyopathies, and multisystemic diseases that are caused by mitochondrial or nuclear DNA defects. Understanding of the phenotypic and genotypic diversity of mitochondrial disease has expanded enormously. In addition, mitochondrial dysfunction is emerging as important in the pathogenesis of a range of conditions including neurodegenerative diseases (Parkinson, Alzheimer, and Huntington diseases), cardiovascular disease, cancer, immunity, and even the aging process. This understanding has challenged the previously held view that mitochondrial diseases are limited to those affecting (directly or indirectly) the proteins of the respiratory chain.
This topic will give a brief overview of mitochondrial structure, function, and genetic attributes.
Clinical aspects of mitochondrial disorders are discussed separately. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
STRUCTURE — Mitochondria are intracellular organelles found in almost all human cells.
Mitochondria are thought to be derived from aerobic bacteria that invaded the proto eukaryotic cell more than a billion years ago and lived in a symbiotic relationship with it, exchanging energy in the form of adenosine triphosphate (ATP) for residence. However, this "endosymbiotic hypothesis" is not universally accepted and has been challenged .
Each human cell contains on average hundreds to thousands of mitochondria. The exception is mature red blood cells, which rely exclusively on anaerobic metabolism and contain no mitochondria.
Although mitochondria were originally represented as individual, isolated organelles it is now recognized that mitochondria form a dynamic connected network (also called a reticulum or syncytium) .
Mitochondria have four main compartments (figure 1):
●The outer membrane, which is permeable to certain ions and small molecules.
●The intermembrane space, which has a composition similar to that of the cytosol.
●The inner membrane, in which are found the respiratory chain proteins. The inner membrane is folded into multiple cristae, allowing for a large surface area.
●The matrix or the inner part of the mitochondrion, where most of the metabolic reactions take place. The mitochondrial DNA is found within DNA-protein complexes, called nucleoids, in the mitochondrial matrix.
FUNCTION — Mitochondria are intracellular organelles that are essential for aerobic metabolism and energy production through oxidative phosphorylation, which is accomplished by the respiratory chain. However, mitochondria are not only the adenosine triphosphate (ATP)-producing "power houses" of the cell. Mitochondria are involved in several other metabolic pathways including beta-oxidation, the Krebs cycle, and the synthesis of iron-sulphur clusters. In addition, mitochondria maintain, replicate, and transcribe their own DNA, and translate messenger RNA (mRNA) into protein. The import and assembly of proteins are also important mitochondrial functions, since most proteins that the mitochondria require are encoded by nuclear DNA and translated in the cytosol. The ongoing remodeling of the mitochondrial network is also a function of the mitochondria. Additional roles of mitochondria in apoptosis, production of reactive oxygen species, calcium homeostasis, maintenance of the lipid membrane and immunity have been described.
The sections that follow provide a brief overview of these diverse functions. For each mitochondrial function, examples of genes associated with mitochondrial disease can be found in the table (table 1) [3-7].
Energy production and metabolism — Mitochondria are the "power houses" of the cell and are the organelles responsible for energy production in the form of ATP, which is the major form of energy for cellular processes (figure 1). Free fatty acids and carbohydrates (in the form of pyruvate) are imported into the mitochondria. Fatty acids cross the outer mitochondrial membrane through carnitine palmitoyltransferase 1 and then cross the inner mitochondrial membrane with the help of carnitine palmitoyltransferase 2. Free fatty acids are metabolized to acetyl-CoA through beta-oxidation in the mitochondrial matrix. Pyruvate is decarboxylated to acetyl-CoA by the pyruvate dehydrogenase enzyme complex. Acetyl-coA then enters the Krebs cycle (also known at the citric acid cycle or the tricarboxylic acid cycle) which also occurs in the mitochondrial matrix. The Krebs cycle oxidizes acetyl-coA to carbon dioxide and water. This produces hydrogen ions which reduce nicotinamide-adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) to NADH and FADH2. Subsequently NADH and FADH2 are used to provide hydrogen ions for the respiratory chain.
Mitochondria are also the site of synthesis of iron-sulfur clusters, which are essential cofactors for respiratory chain complexes I, II, and III as well as aconitase (from the Krebs cycle) . Iron-sulfur clusters synthesis requires ATP, guanosine triphosphate (GTP), NADH and iron.
Respiratory chain — The respiratory chain (also called the electron transport chain) is composed of five enzyme complexes located on the inner mitochondrial membrane (figure 2). Their polypeptides originate from the 13 proteins encoded by mitochondrial DNA (see 'Mitochondrial DNA' below) and from nuclear encoded proteins which are imported into the mitochondria.
●Complex I (NADH dehydrogenase-ubiquinone oxidoreductase) is composed of approximately 46 subunits, seven of which are of mitochondrial origin (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6). Complex I receives electrons from NADH.
●Complex II (succinate dehydrogenase-ubiquinone oxidoreductase) is composed of only four subunits, which are all of nuclear DNA origin. It receives electrons from succinate.
Both succinate and NADH are products of the Krebs cycle. Their electrons are transferred horizontally from complex I and II to a mobile lipid carrier in the inner membrane, co-enzyme Q10, which in turn transfers them to complex III.
●Complex III (ubiquinone-cytochrome c oxidoreductase) is composed of 11 subunits. Only one of them, cytochrome b, is encoded by mitochondrial DNA.
The electrons are transferred from complex III to complex IV by cytochrome c, another protein mobile carrier, in the intermembrane space.
●Complex IV (cytochrome c oxidase) is composed of 13 subunits, three of them (COXI, COXII, and COXIII) of mitochondrial origin. Complex IV uses oxygen as the final electron acceptor to produce water molecules.
●Complex V (ATP synthase) is composed of 16 subunits, two of them (ATP6 and ATP8) from mitochondrial DNA.
Using the energy released by the electron transfers, complexes I, III, and IV pump protons (H+) from the matrix to the intermembrane space, creating an electrochemical proton gradient across the inner membrane. ATP is then generated by complex V when hydrogen protons flow back down their electrochemical gradient to the mitochondrial matrix.
In addition to providing protein subunits for the respiratory chain, nuclear DNA also provides the protein machinery necessary to translate, import and assemble the nuclear-encoded proteins of the respiratory chain . These additional proteins also cause human disease when mutated (table 1).
Mitochondrial DNA replication, maintenance, and transcription — Unlike nuclear DNA, replication and segregation of mitochondrial chromosomes are not coupled to the cell cycle and can occur at any time. Mitochondrial DNA is found within DNA-protein complexes called nucleoids, which are located in the mitochondrial matrix. The proteins required for replication, maintenance, and repair of mitochondrial DNA are also present within the nucleoids . These proteins are encoded by nuclear DNA and are imported into the mitochondria. Dysfunction of these nuclear proteins cause mitochondrial DNA depletion, multiple mitochondrial DNA deletions, and/or site-specific mitochondrial DNA mutations .
Replication of mitochondrial DNA is performed by DNA polymerase gamma (POLG), an accessory subunit encoded by POLG2, twinkle, and DNA2. The substrates for replication include the four deoxynucleoside triphosphates (dATP, dGTP, dCTP, dTTP). Several enzymes controlling the balance of the four deoxynucleoside triphosphates have been implicated in human disease.
Mitochondrial protein synthesis — Mitochondrial DNA is transcribed into 11 mRNAs which are then translated by mitochondrial ribosomes (mitoribosomes) into 13 proteins of the respiratory chain . Translation of these mRNAs into protein is a hugely complex process that occurs inside the mitochondria but relies on the import of an impressive number of nuclear-encoded proteins [10,11]. The nuclear-encoded proteins include:
●Components of the large and small subunits of the ribosome (comprised of 48 and 29 proteins, respectively)
●Translation initiation, elongation and release factors
●Ribosomal protein assembly factors
●mRNA polyadenylation factors
The mitochondrial DNA encodes two of the required ribosomal RNAs. In addition, the 22 mitochondria-encoded transfer RNAs used in translation are post-transcriptionally modified by proteins encoded by the nuclear genome that are also imported into the mitochondria.
Defects of mitochondrial protein synthesis cause a wide phenotypic spectrum of human disease and have so far been described due to mutations in the mitochondrial ribosomal RNAs, mitoribosomal proteins, or in mitoribosomal assembly factors .
Mitochondrial dynamics — Mitochondria are no longer thought to exist as predominantly isolated organelles . Instead, the mitochondrial exist as a dynamic interconnected network (also called a syncytium or reticulum) that is constantly undergoing fusion and fission. The dynamic nature of this ongoing process of remodeling serves to distribute the mitochondrial metabolic capacity and genomes throughout the cell and may have other purposes that are still poorly understood. The processes of fusion and fission involve the dynamin-related proteins, which hydrolyze GTP to provide energy. Fission requires dynamin-related protein 1 (Drp1) and dynamin 2. Endoplasmic reticulum tubules wrap around mitochondria and mark the sites of mitochondrial division. Fusion is performed by mitofusin 1/mitofusin 2 and OPA1. Mitochondrial dynamic abnormalities have been observed in various major neurodegenerative diseases .
Apoptosis — Apoptosis describes a complex and highly regulated process leading to cell death. (See "Apoptosis and autoimmune disease".)
Apoptotic signals such as DNA damage, calcium overload, oxidative stress, and endoplasmic reticulum stress can be transduced to the mitochondria, resulting in opening of the mitochondrial outer membrane and the release of pro-apoptotic factors .
The pro-apoptotic factors contained in the mitochondria include cytochrome c, apoptosis-inducing factor, and second mitochondria-derived activator of caspases. B-cell lymphoma 2 (Bcl-2) family members act as a checkpoint during apoptosis. Bax and Bak are the Bcl-2 protein family members that form the pore in the outer mitochondrial membrane through which the pro-apoptotic factors can be released.
Production of reactive oxygen species — Mitochondria are the main cellular source of reactive oxygen species (ROS) [13,14]. Electrons can be released from the respiratory chain and can combine with oxygen to form superoxide, an ROS. Complex I and III and to a lesser extent Complex II are thought to be the major sites contributing to mitochondrial ROS generation. ROS have multiple effects. They can directly damage (through oxidation) proteins, lipids and nucleic acids. But perhaps more importantly, they act as second messengers in signaling pathways. For example, high levels of ROS production can lead to oxidation of cardiolipin and release of cytochrome c, which triggers the caspase cascade in apoptosis .
Calcium homeostasis — Mitochondria are involved in maintaining calcium homeostasis . Increases in calcium can lead to release of pro-apoptotic factors from mitochondria. In addition, changes in calcium can trigger the opening of the mitochondrial permeability transition pore, which can lead to cell death.
Maintenance of the lipid membrane — The phospholipid membrane of the mitochondria serves as a boundary between the mitochondria and the cytosol, is essential for the electrochemical gradient and the production of ATP, and provides the scaffold for the respiratory chain on the inner mitochondrial membrane [6,15]. Cardiolipin is the major phospholipid of the internal mitochondrial membrane. Tafazzin is a phospholipid-lysophospholipid transacylase and is required for cardiolipin synthesis.
The mitochondrial membrane interacts with the endoplasmic reticulum through specialized lipid raft domains termed MAMs (mitochondria-associated endoplasmic reticulum membranes) [16,17]. MAMs have roles in lipid biosynthesis and transport, calcium signaling, energy metabolism, apoptosis, and mitochondrial dynamics.
The gene encoding choline kinase-beta is an enzyme involved in the biosynthesis of phosphatidylcholine in the MAM. The serine active site-containing protein 1 (SERAC1) is a MAM protein involved in exchange of phospholipids between the endoplasmic reticulum and the mitochondria.
Immunity — Mitochondria have been shown to participate in the innate immune response in several ways .
●Mitochondrial antiviral signaling (MAVS) protein is found on the outer mitochondrial membrane and is required for signaling through retinoic acid-inducible gene I-like receptors (RLR) which are part of the cell's innate immune response to viral infection.
●ROS produced by mitochondria can induce RLR signaling in response to viral infection.
●In the cellular response to bacterial pathogens, mitochondrial ROS production is a result of toll-like receptor 1 activation which promotes translocation of tumor necrosis factor receptor receptor-associated factor 6 (TRAF6) to the mitochondria and its binding to evolutionary conserved signaling intermediate in Toll pathways (ECSIT) on the outer mitochondrial membrane.
●ROS can directly kill bacteria or activate the NF-kappa B and mitogen-activated protein kinases (MAPK) signaling pathway, which cumulates in pro-inflammatory cytokine production. Interferon gamma signaling can increase mitochondrial ROS production.
●Mitochondrial can participate in the immune response by providing damage associated molecular patterns (DAMPs) which activate signaling pathways in response to cellular damage. Some examples of mitochondrial DAMPs include mitochondrial DNA, mitochondrial ATP, N-formyl peptides, and mitochondrial transcription factor A.
●Mitochondria can activate the NLRP3 inflammasome (a multimeric complex which can activate caspase 1 and promote the production of cytokines), mainly through production of ROS.
●Mitochondria participate in antigen presentation on major histocompatibility complex (MHC) class I molecules in macrophages and dendritic cells .
MITOCHONDRIAL GENETICS — Mitochondria are under the dual control of nuclear DNA and mitochondrial DNA [19,20]. It was once believed that nuclear DNA disorders tended to present in childhood while mitochondrial DNA disorders (whether primary or secondary to nuclear DNA abnormalities) tended to present in late childhood or adulthood. However, it is now clear that both mitochondrial and nuclear DNA disorders can present throughout life . Estimates from Northern England suggest that the prevalence of disorders of mitochondrial DNA and nuclear DNA is 20 and 2.9 per 100,000 persons, respectively . Overall, this indicates of prevalence of 1 in 4300 for mitochondrial diseases caused by either mitochondrial or nuclear mutations.
Mitochondrial DNA — While the nuclear genome is diploid, harboring only two homologous copies of each chromosome (one paternal and one maternal) the mitochondrial genome is polyploid, containing 1 to 10 identical molecules of mitochondrial DNA within its matrix. This variable copy number, combined with the variable number of mitochondria in each cell, has important implications for the phenotypic expression of a mutation. (See 'Heteroplasmy' below.)
Mitochondrial DNA is a double-stranded closed circular molecule, composed of 16,569 base pairs, that codes for 13 polypeptide units, all of which are components of the respiratory chain. However, each mitochondrion has approximately 1700 gene products, including over 200 respiratory chain proteins . Thus, the great majority of these are encoded by nuclear DNA. (See 'Nuclear DNA' below.)
The mitochondria have their own machinery for DNA transcription and RNA translation. In addition to 13 polypeptide genes, mitochondrial DNA encodes for 22 transfer RNAs and 2 ribosomal RNAs, giving a total of 37 mitochondrial genes. The genetic code of mitochondrial DNA differs slightly from the universal genetic code of nuclear DNA in that certain mitochondrial trinucleotides encode different amino acids or stop codons than those in the universal genetic code.
In addition to a different genetic code, mitochondrial DNA has several characteristics that distinguish it from nuclear DNA . These unique characteristics of mitochondrial DNA are summarized below.
Mutation rate — Mitochondrial DNA has a high mutation rate due to the lack of histones and to damage from oxygen radical species. Many point mutations as well as insertions, deletions, duplications and rearrangements of varying size and complexity have been reported [25,26].
Maternal inheritance — One of the most distinctive features of mitochondrial DNA is that of maternal inheritance. During oocyte fertilization, the sperm brings only a small quantity of mitochondria, approximately 100 times less than the oocyte . In addition, the paternal mitochondria are diluted with subsequent cell divisions and mitotic segregation. Furthermore, some paternal mitochondria are targeted and destroyed, possibly through ubiquitination . (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Causes of non-Mendelian inheritance'.)
Thus, a fertilized egg possesses mitochondria derived predominantly from the mother, so that the mitochondrial genotype is essentially only transmitted through the mother. While paternal mitochondria transmission in animals does occur , there has been only one reported human case of paternal transmission in muscle cells .
A shift in mitochondrial mutation load may be seen in the offspring of mothers affected by mitochondrial DNA mutations. This shift is a result of the restriction-amplification event that occurs during oocyte maturation and it is termed the mitochondrial bottleneck effect. During the production of primary oocytes, a small proportion of the total mitochondria in the primordial germ cell is randomly segregated into each primary oocyte (ie, restriction) . With maturation, there is rapid replication (ie, amplification) of the mitochondrial DNA in each primary oocyte. Thus, the mature oocyte may contain a different proportion of mutant mitochondrial DNA compared with the proportion found in the primordial germ cell.
Sporadic mutations of mitochondrial DNA can also occur in the germ cells, leading to offspring with different mitochondrial DNA composition than their mothers.
Heteroplasmy — Each mitochondrion has several DNA molecules, and each cell has several hundred mitochondria. In a normal state, all these mitochondrial DNAs are identical (homoplasmy). When a pathogenic mutation ensues, it is generally present in some but not all of these mitochondrial DNA copies (heteroplasmy).
Heteroplasmy can apply to a single mitochondrion (ie, some pathologic DNA copies mixed with normal ones within one mitochondrion), to the cell (ie, healthy mitochondria mixed with mitochondria harboring mutated DNA) or to specific tissues (ie, some pathologic cells mixed with healthy ones).
It was once believed that all pathogenic mutations are heteroplasmic. This view is no longer accepted, as homoplasmic mutations have been found to cause disease . Similarly, nonpathogenic haplotype differences are usually but not always homoplasmic.
Threshold effect — Given variable mitochondrial heteroplasmy, not all cells in a tissue are abnormal. As a consequence, a minimal number of mutated DNAs must be present before respiratory chain failure and cellular dysfunction occur. Clinical signs do not become apparent until enough cells are affected. This is known as the threshold effect.
The threshold varies between different body tissues but is lower in tissues mainly relying on oxidative phosphorylation for energy production, such as the brain, the retina, the skeletal muscles, and the heart. This explains why systemic mitochondrial defects often manifest clinically in these organs. Furthermore, the amount of heteroplasmy (or "mutation load") in a specific tissue often correlates with severity of the illness in that tissue . In most mitochondrial disorders with overt disease, the mutation load is quite high, generally ≥80 percent .
Mitotic segregation — Mitochondria are randomly distributed at the time of cell division, which can lead to a change in the amount of mutant DNA in a cell and surpass its threshold. The clinical phenotype can then change in a previously unaffected tissue.
Postmitotic replication — Mitochondrial DNA replication is not linked to the cell cycle. This allows for postmitotic mitochondrial DNA replication in terminally differentiated cells such as neurons or muscle in response to specific stimuli (exercise, increased metabolic demand). This explains how the symptomatic threshold can be exceeded later in life in previously asymptomatic tissues.
Nuclear DNA — Each mitochondrion has approximately 1700 proteins, including more than 200 respiratory chain proteins . The great majority of these are encoded by nuclear DNA and synthesized in the cytosol, then imported to the mitochondrion. The only exceptions are the 13 polypeptide components of the respiratory chain encoded by mitochondrial DNA. (See 'Mitochondrial DNA' above.)
In contrast to mitochondrial DNA, nuclear DNA mutations affecting the mitochondria follow Mendelian genetics and are inherited in an autosomal dominant, autosomal recessive, or X-linked pattern (see "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)"). De novo mutations (ie, sporadic inheritance) are also described.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mitochondrial disorders".)
●Dynamics – Nearly every human cell type contains hundreds to thousands of mitochondria. Mitochondria form a dynamic interconnected network, constantly undergoing fusion and fission. (See 'Mitochondrial dynamics' above.)
●Function – The main role of mitochondria is energy production via oxidative phosphorylation, which takes place along the inner mitochondrial membrane. The respiratory chain is composed of five enzyme complexes (figure 2). (See 'Energy production and metabolism' above and 'Respiratory chain' above.)
Mitochondria also participate in diverse cellular processes:
•Apoptosis (see 'Apoptosis' above)
•Production of reactive oxygen species (see 'Production of reactive oxygen species' above)
•Calcium homeostasis (see 'Calcium homeostasis' above)
•Immunity (see 'Immunity' above)
●Genetics– Mitochondria are under the dual control of mitochondrial and nuclear DNA. Mitochondria contain their own machinery for mitochondrial DNA replication, maintenance, transcription, and translation. Of the estimated 1700 proteins required for mitochondrial function, only 13 proteins, 22 transfer RNAs, and 2 ribosomal RNAs are encoded by mitochondrial DNA. The remaining proteins required for mitochondrial function are encoded by nuclear DNA, are transcribed and translated in the cytosol, and are then imported into the mitochondria. (See 'Mitochondrial genetics' above and 'Mitochondrial DNA' above and 'Nuclear DNA' above.)
●Mitochondrial DNA – Mitochondrial DNA has several unique characteristics that distinguish it from nuclear DNA including:
•Maternal inheritance (see 'Maternal inheritance' above)
•Heteroplasmy (see 'Heteroplasmy' above)
•The threshold effect (see 'Threshold effect' above)
•Random partitioning during mitotic segregation (see 'Mitotic segregation' above)
•Postmitotic replication (see 'Postmitotic replication' above)
●Clinical disorders – Mitochondrial disease may result from defects in any of the above-described functions (table 1). Mitochondrial disorders may be transmitted by autosomal recessive, autosomal dominant, maternal, X-linked, or sporadic inheritance and can present at any age. Mitochondrial diseases are remarkable for their wide phenotypic and genetic heterogeneity. (See 'Mitochondrial genetics' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Rami Massie and Angela Genge, MD, who contributed to earlier versions of this topic review.
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