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Mitochondrial regulation and functions

Mitochondrial regulation and functions
Literature review current through: Jan 2024.
This topic last updated: Jan 24, 2024.

INTRODUCTION — Mitochondrial abnormalities may be seen in primary mitochondrial disorders (chronic, genetically determined disorders in which the primary problem is mitochondrial dysfunction) as well as acquired conditions with mitochondrial dysfunction (such as due to other medical conditions or medications). Primary mitochondrial disorders can be caused by pathogenic variants in genes in nuclear DNA or mitochondrial DNA (mtDNA).

This topic will give a brief overview of mitochondrial structure, regulation, genetics, and functions.

Mitochondrial disorders are discussed in separate topic reviews listed in the sections below. (See 'Primary mitochondrial disorders' below and 'Disorders with altered mitochondrial function' below and 'Drug-induced mitochondrial disorders' below.)

TYPES OF MITOCHONDRIAL DISORDERS

Prevalence — Estimates from Northern England suggest that the prevalence of mitochondrial disorders due to pathogenic variants in nuclear DNA is 2.9 per 100,000 and due to pathogenic variants in mitochondrial DNA (mtDNA) is 20 per 100,000 persons [1]. Overall, this indicates a prevalence of 1 in 4300 for mitochondrial diseases caused by pathogenic variants in nuclear or mtDNA.

It was once believed that nuclear DNA disorders tended to present in childhood while mtDNA disorders (whether primary or secondary to nuclear DNA abnormalities) tended to present in late childhood or adulthood. However, it is now clear that both nuclear DNA and mtDNA disorders can present throughout life [2].

Primary mitochondrial disorders — Primary mitochondrial diseases are genetically determined disorders in which mitochondrial dysfunction is responsible for the clinical disorder. They can be caused by pathogenic variants affecting germline nuclear DNA or mtDNA. (See 'Mitochondrial genetics' below.)

These encompass several types of clinical phenotypes based on which organ system(s) are affected:

Myopathies

Neurologic diseases (including encephalomyopathies, neuropathies, and ataxias)

Multisystemic diseases

The high mutation rate in mtDNA is discussed below. (See 'High mutation rate and variable phenotypic expression' below.)

Details of evaluation and management are presented separately:

Myopathies and encephalomyopathies – (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Mitochondrial disorders: Treatment".)

Neuropathies – (See "Neuropathies associated with hereditary disorders", section on 'Mitochondrial disorders'.)

Cerebellar ataxias – (See "Overview of the hereditary ataxias", section on 'Mitochondrial ataxias'.)

Amyotrophic lateral sclerosis – (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Pathology'.)

Pearson syndrome – (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Pearson syndrome' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Pearson syndrome (large deletion of mitochondrial DNA)'.)

Mitochondrial disorders causing systemic disease – (See "Inborn errors of metabolism: Classification", section on 'Mitochondrial disorders'.)

Understanding of the phenotypic and genotypic diversity of mitochondrial disease has expanded enormously. 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. Primary mitochondrial diseases now include diseases affecting other mitochondrial functions including mitochondrial dynamics (fission & fusion), apoptosis, mitochondrial membrane homeostasis, nonrespiratory pathways, and others (table 1) [3-7].

Disorders with altered mitochondrial function — Mitochondrial dysfunction is emerging as important in the pathogenesis of a variety of conditions including:

Neurodegenerative diseases (Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis)

Cardiovascular disease

Cancer

Immunity

Liver disease

Traumatic brain injury

Stroke (ischemia and reperfusion)

Autoimmune disease (systemic lupus erythematosus [SLE], rheumatoid arthritis)

Wound healing

Aging

These conditions are not primary mitochondrial disorders, and they may have multiple mechanisms that include cellular functions independent of mitochondria or that impact mitochondria only indirectly. However, they illustrate how mitochondria play a role in a wide variety of human diseases.

For neurodegenerative disorders, the pathogenesis appears to involve oxidative stress, among other mechanisms, as discussed in detail separately. (See "Epidemiology, pathogenesis, and genetics of Parkinson disease", section on 'Mitochondrial dysfunction' and "Prevention of dementia", section on 'Antioxidant vitamins' and "Huntington disease: Genetics and pathogenesis", section on 'Mutant huntingtin'.)

Roles of mitochondria in immunity and aging are discussed below. (See 'Inflammation and immunity' below and 'Role in aging' below.)

Drug-induced mitochondrial disorders — Certain antiviral or antibacterial drugs target mitochondrial function.

Selected examples are discussed separately:

Antiviral reverse transcriptase inhibitors. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors".)

Antibacterial therapies. (See "Linezolid and tedizolid (oxazolidinones): An overview", section on 'Adverse effects'.)

STRUCTURE AND REGULATION

Origin — Mitochondria are intracellular organelles 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 inside the cell and use of cellular proteins [8]. However, this "endosymbiotic hypothesis" is not universally accepted and has been challenged [9].

Distribution — Mitochondria are found in virtually every cell type in the human body, on average hundreds to thousands of mitochondria per cell [10]. The only cells lacking mitochondria are mature red blood cells (RBCs), which rely exclusively on anaerobic glycolysis for energy production. Mitochondria are extruded from RBCs, along with the cell nucleus, during the later stages of normoblast maturation [11]. (See "Rare RBC enzyme disorders", section on 'Glycolysis pathway' and "Regulation of erythropoiesis", section on 'Precursors and mature cells'.)

Mitochondria are reported to be especially abundant in cells with high metabolic requirements, including muscle, nerve, liver, and kidney [9].

Sperm contain approximately 50 to 75 mitochondria that generate energy to power sperm motility, but these are selectively destroyed shortly after fertilization [12]. (See "Male reproductive physiology", section on 'Spermatogenesis'.)

Membrane and functional compartments — Mitochondria have four main compartments bounded by phospholipid membranes (figure 1):

Outer membrane – Serves as a boundary between the mitochondria and the cytosol. It is permeable to certain ions and small molecules.

Inner membrane – It is folded into multiple cristae, allowing for a large surface area. It is the site of the respiratory chain proteins. It is essential for the electrochemical gradient and the production of ATP, and it provides the scaffold for the respiratory chain on the inner mitochondrial membrane [6,13]. (See 'Metabolism and ATP production' below.)

Cardiolipin is the major phospholipid of the internal mitochondrial membrane. Tafazzin is a phospholipid-lysophospholipid transacylase required for cardiolipin synthesis. Anticardiolipin antibodies are a type of autoantibody seen in antiphospholipid syndrome. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Antiphospholipid antibodies'.)

Intermembrane space – Has a composition similar to that of the cytosol. Multiple transmembrane transport systems regulate the exchange of calcium ions, sodium ions, and protons between the matrix and the cystosol [14]

Matrix – This inner part of the mitochondrion is where the mitochondrial DNA (mtDNA) is located and where most of the metabolic reactions take place. (See 'Mitochondrial DNA, RNA, and protein synthesis' below.)

The mitochondrial membrane interacts with the endoplasmic reticulum through specialized lipid raft domains termed MAMs (mitochondria-associated endoplasmic reticulum membranes) [15,16]. MAMs have roles in lipid biosynthesis and transport, calcium signaling, energy metabolism, apoptosis, and mitochondrial dynamics.

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.

Fusion and fission dynamics — While mitochondria were initially presumed to exist as predominantly isolated organelles, this is no longer thought to be the case [8]. Instead, the mitochondria 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 remodeling process distributes 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. These are encoded by nuclear genes. 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 [17].

Relationship between mitochondrial division and the cell division cycle — Unlike nuclear DNA, replication and segregation of mitochondrial DNA is not coupled to the cell division cycle and can occur at any time. This allows for postmitotic mitochondrial DNA replication in terminally differentiated cells such as neurons or muscle and in response to specific stimuli (exercise, increased metabolic demand).

There are two ways in which pathogenic variants in mitochondrial genes can exceed the symptomatic threshold in a previously unaffected tissue (see 'Threshold effect' below):

Postmitotic mitochondrial DNA replication can result in expansion of a population of mitochondria carrying the pathogenic variant.

Random distribution of mitochondria within the cell cytoplasm can result in an abundance of mitochondria carrying the pathogenic variant in one of the daughter cells following mitosis, to the point that the level surpasses the threshold.

The clinical phenotype can then change in a previously unaffected tissue later in life.

Mitochondrial DNA, RNA, and protein synthesis

Circular genome Mitochondrial DNA (mtDNA) consists of a single, 16,569 base pair double-stranded circular DNA molecule (figure 2) that encode 13 proteins, as well as genes for two transfer RNAs and 22 ribosomal RNAs, for a total of 37 mitochondrial genes in a structure called a nucleoid [8,18-20]. Of the estimated 1700 proteins required for mitochondrial function, only these 13 proteins, two ribosomal RNAs, and 22 transfer RNAs are encoded by mtDNA; the remainder are encoded by the nuclear genome. (See 'Mitochondrial genetics' below.)

Nucleoids – Each nucleoid contains one or two mtDNA molecules complexed with regulatory proteins, and each mitochondria contains approximately three nucleoids (most only contain one) [21]. These nucleoids are located in the mitochondrial matrix.

Rather than the typical structure of eukaryotic nuclear chromosomes (with a centromere, paired sister chromatids with long and short arms, and telomeres), mtDNA is more similar to a bacterial chromosome in being circular. mtDNA also lacks histones, which are present in nuclear chromosomes; histones allow condensation and compaction of DNA, protect certain regions of the DNA sequence, and regulate transcription. (See "Principles of epigenetics", section on 'Histone modifications'.)

However, like nuclear chromosomes, the DNA is complexed with proteins required for replication, maintenance, and repair of the mtDNA [8]. The proteins are encoded by genes in the cell nucleus that are imported into mitochondria.

Transcription – Mitochondria have their own machinery for DNA transcription and RNA translation. The polymerase used for mt DNA replication is DNA polymerase gamma (PolG, encoded by nuclear genes POLG [polymerase], POLG2 [accessory subunit], TWNK [DNA helicase] and DNA2 [helicase/nuclease]). Pathogenic variants in these nuclear genes can cause mtDNA depletion, deletions, and/or site-specific mutations [6].

The substrates for replication include the four deoxynucleoside triphosphates (dNTPS: dATP, dGTP, dCTP, dTTP). Pathogenic variants affecting the enzymes controlling the balance of the four dNTPs have been implicated in human diseases.

The 11 mtDNA genes are transcribed into 11 mRNAs, which are then translated by mitochondrial ribosomes (mitoribosomes) into 13 proteins of the respiratory chain, used to produce energy in the form of ATP (adenosine triphosphate) [6]. (See 'Metabolism and ATP production' below.)

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. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Gene expression'.)

Translation machinery – 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 including [22,23]:

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

Translational activators

Two of the required ribosomal RNAs are encoded by mtDNA. 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.

Abnormalities 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 [22].

CELLULAR FUNCTIONS — Mitochondria are involved in aerobic metabolism, energy production in the form of ATP (adenosine triphosphate), and several other metabolic pathways discussed below.

Metabolism and ATP production — Mitochondria are the "powerhouses" of the cell. They are essential for aerobic metabolism and production of ATP, the main source of energy for all cellular processes.

The metabolic pathways are illustrated in the figure (figure 1).

Substrates for metabolism – The initial source of substrates for metabolism are free fatty acids and carbohydrates (in the form of pyruvate), which 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 provide hydrogen ions for the respiratory chain.

Iron sulfur clusters – Iron-sulfur clusters are essential cofactors for respiratory chain complexes I, II, and III as well as aconitase (from the Krebs cycle) (figure 3) [24].

Iron-sulfur clusters are synthesized within the mitochondria, in a process requiring 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 4). The proteins in the respiratory chain are encoded by mitochondrial DNA (mtDNA) and nuclear DNA. In addition to providing protein subunits for the respiratory chain, nuclear DNA also provides the protein machinery necessary to translate, import, and assemble these nuclear-encoded proteins [25]. Pathogenic variants in these nuclear genes can also cause mitochondrial disease (table 1). (See 'Mitochondrial genetics' below.)

Complex I (NADH dehydrogenase-ubiquinone oxidoreductase) – Contains approximately 46 subunits, seven of which are of mtDNA origin (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6). Complex I receives electrons from NADH.

Complex II (succinate dehydrogenase-ubiquinone oxidoreductase) – Contains four subunits, all of nuclear DNA origin. Complex II receives electrons from succinate.

NADH and succinate are both 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) – Contains 11 subunits. Only one, cytochrome b, is encoded by mtDNA. 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) – Contains 13 subunits, three of mtDNA origin (COXI, COXII, and COXIII). Complex IV uses oxygen as the final electron acceptor to produce water molecules.

Complex V (ATP synthase) – Contains 16 subunits, two of mtDNA origin (ATP6 and ATP8).

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 protons flow back down their electrochemical gradient to the mitochondrial matrix.

The respiratory chain can also generate reactive oxygen species (ROS) via interactions of electrons with molecular oxygen to form superoxide, a type of ROS [26,27]. 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, including direct damage of proteins, lipids and nucleic acids (through oxidation), and acting as second messengers for apoptosis pathways. (See 'Apoptosis' below.)

Apoptosis — Apoptosis describes a complex and highly regulated form of cell death distinct from necrosis.

Mitochondria can regulate apoptosis by at least two pathways [28]:

Apoptosis involving the BCL-2, BAX, and caspase apoptosis pathway. (See "Apoptosis and autoimmune disease", section on 'Molecular mechanisms of apoptosis'.)

Mitochondrial transition-driven necrosis [28].

Apoptotic signals such as DNA damage, calcium excess, oxidative stress, and endoplasmic reticulum stress can be transduced to the mitochondria, resulting in opening of the mitochondrial outer membrane and the release of proapoptotic factors [26]. Reactive oxygen species (ROS) produced by mitochondria can lead to oxidation of cardiolipin and release of cytochrome c, which triggers the caspase cascade [26].

The proapoptotic factors contained in the mitochondria include cytochrome c, apoptosis-inducing factor, and second mitochondria-derived activator of caspases. 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.

Calcium homeostasis — Mitochondria are involved in maintaining calcium homeostasis [26]. Increases in calcium can lead to release of proapoptotic factors from mitochondria and can trigger the opening of the mitochondrial permeability transition pore, which can lead to cell death. (See 'Apoptosis' above.)

Inflammation and immunity — Mitochondria have been shown to participate both in the innate immune response [27,29]. Similar pathways appear to be activated in autoimmune diseases [28].

More than a dozen distinct but potentially interconnected pathways can result in:

Immune activation – By production of interleukins and tumor necrosis factor (TNF).

Chemotaxis and activation of immune cells – Including antigen presenting cells, neutrophils, dendritic and gamma-delta cells.

Activation of apoptosis – The NLRP3-inflammasome (multimeric complex that can activate caspase 1 and promote cytokine production), and mitophagy pathways.

DAMPs – Release or degradation of mitochondrial danger-associated molecular patterns (DAMPs) activates signaling pathways in response to cellular damage. Mitochondrial DAMPs include mtDNA, mitochondrial ATP, N-formyl peptides, and mitochondrial transcription factor A. (See "An overview of the innate immune system", section on 'Damage-associated molecular patterns'.)

Antigen presentation – Occurs on major histocompatibility complex (MHC) class I molecules in macrophages and dendritic cells [30].

The following are examples of how these pathways can be involved in specific infectious or inflammatory processes:

Viral infections – Mitochondrial antiviral signaling (MAVS) protein is located on the outer mitochondrial membrane and is required for signaling through retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), which are part of the cell's innate immune response to viral infection. Reactive oxygen species (ROS) produced by mitochondria can induce RLR signaling in response to viral infection.

Bacterial infections – In the cellular response to bacterial pathogens, toll-like receptor 1 activation promotes translocation of tumor necrosis factor receptor-associated factor 6 (TRAF6) to the mitochondria and binding to evolutionary conserved signaling intermediate in Toll pathways (ECSIT) on the outer mitochondrial membrane, in turn leading to mitochondrial ROS production. ROS can directly kill bacteria or activate the NF-kappa B and mitogen-activated protein kinase (MAPK) signaling pathways, which cumulate in pro-inflammatory cytokine production. Interferon gamma signaling can increase mitochondrial ROS production.

Role in aging — Mitochondrial dysfunction is considered to be a hallmark of aging, and age-related changes in mitochondrial function may contribute to frailty [31]. (See "Normal aging", section on 'Molecular basis of aging' and "Frailty", section on 'Other stress response and metabolic systems'.)

MITOCHONDRIAL GENETICS — Mitochondria are under the dual control of nuclear DNA and mitochondrial DNA (mtDNA) [32,33].

Nuclear genes — Each mitochondrion has approximately 1700 proteins, including more than 200 respiratory chain proteins [34]. All but 13 of these are encoded by nuclear DNA and synthesized in the cytosol, then imported to the mitochondrion. mtDNA only encodes 13 proteins involved in the respiratory chain and some regulatory RNAs. (See 'Mitochondrial DNA, RNA, and protein synthesis' above.)

Pathogenic variants in nuclear genes that affect mitochondrial function follow Mendelian inheritance patterns (autosomal dominant, autosomal recessive, or X-linked). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mendelian inheritance patterns'.)

Mitochondrial genes — The circular double stranded mitochondrial DNA (mtDNA) contains 11 protein-coding genes that are transcribed into 13 proteins (figure 2). In addition, mtDNA encodes for 22 transfer RNAs and 2 ribosomal RNAs, giving a total of 37 mitochondrial genes. (See 'Mitochondrial DNA, RNA, and protein synthesis' above.)

Maternal inheritance — One of the most distinctive features of mtDNA is maternal inheritance. During oocyte fertilization, the sperm brings only a small quantity of mitochondria, approximately 100 times less than the oocyte [35]. With subsequent cell divisions, paternal mitochondria are diluted and/or targeted and destroyed, possibly through ubiquitination [36]. As a result, all the mitochondria in the offspring come almost exclusively from the maternal line. Evidence from animals suggests that paternal mitochondria transmission does occur [37]; however, there has been only one reported human case of paternal transmission in muscle cells [38].

Additional details of maternal inheritance are presented separately. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mitochondrial inheritance'.)

Females with primary mitochondrial disorders due to variants in mitochondrial genes who wish to have offspring lacking the disorder can undergo in vitro fertilization with techniques using donor egg mitochondria and maternal nuclear DNA. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'Other uses'.)

High mutation rate and variable phenotypic expression — mtDNA has a higher mutation rate than nuclear DNA. This is due to the lack of histones, which have a protective function, and the abundance of oxygen radicals that can cause DNA damage. (See 'Metabolism and ATP production' above.)

Many point mutations, as well as insertions, deletions, duplications, and rearrangements of varying size and complexity have been reported [39,40]. (See 'Primary mitochondrial disorders' above.)

While the nuclear genome is diploid, containing only two homologous copies of each chromosome (one paternal and one maternal), the mitochondrial genome is polyploid, containing 1 to 10 molecules of mitochondrial DNA within its matrix. This variable copy number, combined with the variable number of mitochondria in each cell (see 'Distribution' above), has important implications for the phenotypic expression of a mutation. (See 'Heteroplasmy' below.)

A shift in mitochondrial mutation load may be seen in the offspring of mothers affected by pathogenic variants in mtDNA. This shift is a result of the restriction-amplification event that occurs during oocyte maturation and it is termed the mitochondrial bottleneck effect.

Restriction – During the meiotic cell division that produces primary oocytes, a small proportion of the total mitochondria in the primordial germ cell is randomly segregated into each primary oocyte (ie, restriction) [41]. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Meiosis'.)

Amplification – 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 a variant in mtDNA compared with the proportion found in the primordial germ cell.

Sporadic mutations of mtDNA can also occur in the germ cells, leading to a different mtDNA composition than that in maternal cells.

Heteroplasmy — Each mitochondrion has several DNA molecules, and each cell has several hundred to 1000 mitochondria. In a normal state, all these mtDNAs are identical (homoplasmy). When a pathogenic mutation occurs, it is generally present in some but not all of these mtDNA copies (heteroplasmy).

Heteroplasmy can apply to a single mitochondrion (some pathologic variants mixed with wildtype versions of the gene within one mitochondrion), to the cell (unaffected mitochondria mixed with mitochondria carrying the pathogenic variant), or to specific tissues (some affected cells mixed with some unaffected cells).

It was once believed that all pathogenic variants are heteroplasmic. This view is no longer accepted, as homoplasmic pathogenic variants have been found to cause disease [42]. Similarly, benign variants are usually but not always homoplasmic. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)

Threshold effect — Given variable mitochondrial heteroplasmy, not all cells in a tissue will be affected by a pathogenic variant in a mitochondrial gene. As a consequence, a minimal number of affected mtDNA molecules 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. It 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 [43]. In most mitochondrial disorders with overt disease, the mutation load is quite high, generally ≥80 percent [34].

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".)

SUMMARY

Primary mitochondrial diseases – Primary mitochondrial diseases are genetically determined disorders in which mitochondrial dysfunction is responsible for the disorder. They include myopathies, encephalomyopathies, and multisystemic diseases (table 1). They can be caused by pathogenic variants in germline nuclear DNA or mitochondrial DNA (mtDNA). The overall prevalence is approximately 1 in 4300. (See 'Primary mitochondrial disorders' above and 'Prevalence' above.)

Other causes of mitochondrial dysfunction – A range of human conditions exhibit mitochondrial dysfunction, including neurodegenerative, cardiovascular, cancer, immune, hepatic, and autoimmune disorders. Certain medications (antiviral reverse transcriptase inhibitors, antibiotics) can cause mitochondrial dysfunction. (See 'Disorders with altered mitochondrial function' above and 'Drug-induced mitochondrial disorders' above.)

Structure and regulation – Mitochondria are derived from aerobic bacteria that invaded the proto eukaryotic cell over a billion years ago. They are present in all eukaryotic cells except mature red blood cells and are especially abundant in cells with high energy demands (hundreds to thousands per cell). They have four main compartments (figure 1) and form a dynamic interconnected network undergoing fusion and fission. Their circular double-stranded genome encodes 13 proteins of the respiratory cascade (figure 2), plus genes for transfer and ribosomal RNAs. mtDNA replication is independent of the cell division cycle. (See 'Structure and regulation' above.)

Functions – Mitochondria are the powerhouses of the cell, producing energy in the form of ATP (adenosine triphosphate) via the Krebs cycle, fatty acid oxidation, and oxidative phosphorylation (figure 4). They also have roles in apoptosis, calcium homeostasis, inflammation and immunity, and aging. (See 'Cellular functions' above.)

Genetics

Nuclear genes – Primary mitochondrial diseases due to pathogenic variants in nuclear genes follow Mendelian inheritance patterns (autosomal dominant, autosomal recessive, or X-linked). (See 'Nuclear genes' above.)

Mitochondrial genes – Mitochondrial genes exhibit maternal inheritance since only the oocyte provides mitochondria for the developing embryo. mtDNA has a higher mutation rate than nuclear DNA due to lack of protective histones and presence of abundant DNA-damaging oxygen radicals. When a pathogenic mutation occurs, it is generally present in a subset of mtDNA copies (heteroplasmy), which can apply to the mitochondrion, cell, or tissue. This in turn produces a threshold effect, in which clinical signs do not become apparent until a threshold number of cells are affected. (See 'Mitochondrial genes' 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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Topic 5148 Version 20.0

References

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