Defects of mitochondrial metabolism cause a wide range of human diseases that include examples from all medical subspecialties. The origin of somatic mtdna mutations in human cancer and their potential diagnostic and therapeutic implications in. Mitochondrial dna variation in human evolution and disease. The circular, doublestranded human mitochondrial genome is depicted with sites of common mtdna mutations highlighted. Mitochondrial dna mutations in human disease request pdf. In spite of tremendous progress in mitochondrial biology since the causeandeffect relations between mtdna mutation and the human diseases. Compared with nuclear dna, mitochondrial dna is at least 10 times more vulnerable to mutation. Here, we examine the evidence supporting a causative role for mtdna mutations in mammalian aging. Mitochondrial dna mutations in aging, disease and cancer. The clinical phenotype resulting from mtdna mutations. It is well established that certain nucleoside reverse transcriptase inhibitor nrti antiretroviral drugs cause inhibition of.
Heteroplasmic mutations can cause mitochondrial diseases and are involved in cancer and aging, but they are also common in healthy people. The small, maternally inherited mitochondrial dna mtdna has turned out to be a pandoras box of pathogenic mutations. Mitochondrial dna mutations and human disease sciencedirect. Mitochondrial dna mutations in the pathogenesis of human. Jci mitochondrial dna mutations in human colonic crypt. Mutations of mtdna cause a variety of human mitochondrial.
Human mitochondrial dna is a 16,569 bp circle of double stranded dna that encodes essential respiratory chain subunits. Twinkle and other human mitochondrial dna helicases. Since the first identification of mitochondrial dna mtdna defects responsible for human diseases in 1988, it has been increasingly clear that mutations in the mtdna. Missense mutations in the mitochondrial electrontransport genes cause leber hereditary optic neuropathy.
A relationship between mitochondrial dysfunction and a wide range of disease states was known to exist, but whether mitochondrial dysfunction was responsible for the particular disease was still in question. Mitochondrial dna mutations in diseases of energy metabolism. Jan 01, 2003 by engineering mice that rapidly accumulate mitochondrial dna mutations in the heart, we have a convenient model to study the pathogenesis of mtdna mutations. The human mitochondrial genome is extremely small compared with the nuclear genome, and. The mutation frequency in the hearts of these mice was comparable to that reported in diseases and in aging 23, and these mice developed heart disease. These include missense mutations in most of the mtdna polypeptide genes as well as base substitutions in several trna genes. Mammalian mitochondria contain a circular genome mtdna which encodes subunits of the oxidative phosphorylation machinery. The mitochondrial dna mtdna depletion syndrome mds is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtdna copy number in affected. Somatic acquired mtdna mutations are also associated with degenerative diseases and with normal human ageing. The differences between the two genetic systems that are in human cells are probably a relic of. Mtdna mutations were marked in several pathogenic disorders including mitochondrial myopathy, strokelike attacks, encephalopathy and maternally hereditary diabetes 4. Diseasecausing mutations in mitochondrial dna mtdna are typically heteroplasmic and therefore interpretation of genetic tests for mitochondrial disorders can be problematic. A proposed refinement of the mitochondrial free radical theory of aging.
May 01, 2015 the mitochondrial dna mtdna depletion syndrome mds is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtdna copy number in affected tissues without mutations or rearrangements in the mtdna. Because they provide 30 molecules of atp per glucose molecule in contrast to the 2 atp molecules produced by glycolysis, mitochondria are essential to all. Mitochondrial encephalomyopathies are highly variable both clinically and at the genetic level 3. Mitochondrial dna mtdna mutations cause inherited diseases and are implicated in the pathogenesis of common lateonset disorders, but how they arise is not clear1,2. The important characteristics of human mtdna are as follows. Chronification of inflammation is the process that lies at the basis of several human diseases that make up to 80% of morbidity and mortality worldwide. The biology of mitochondrial disease archives of disease. There have been four other diseasecausing mutations found in. Mitochondrial dna mutations activate the mitochondrial. Mitochondrial dna mtdna accumulates both basesubstitution mutations and deletions with aging in several tissues in mammals. Here, we examine the evidence supporting a causative role for mtdna. Mechanisms of disease and evolution a team of israeli life scientists is intensively investigating mitochondrial dna and its relationship to two phenomena determined by the same principles. Until recently, mitochondrial genetics and diseases that are due to defects in. Mitochondrial dna mutations in the pathogenesis of human disease.
Introduction of disease related mitochondrial dna deletions into hela cells lacking mitochondrial dna results in mitochondrial dysfunction. How can mutations in mitochondrial dna affect the human body. Mitochondrial disorders may be caused by mutations acquired or inherited, in mitochondrial dna, or in nuclear genes that code for mitochondrial components. Thus, human mitochondrial diseases encompass mutations of mtdna and nuclear dna, as well as toxininduced defects. A buildup of somatic mutations in mitochondrial dna has been associated with an increased risk of certain agerelated disorders such as heart disease, alzheimer disease, and. Mitochondrial dna mutations in human colonic crypt stem cells robert w. The cellular mitochondrial genome landscape in disease. Mitochondrial genetics is different from mendelian genetics in almost every aspect, from the uniparental inheritance of disease mutations, to the presence of many copies of the genome within a single cell. Mitochondrial diseases in humans the embryo project. Since the first identification of mitochondrial dna mtdna defects responsible for human diseases in 1988, it has been increasingly clear that mutations in the mtdna represent an important cause of neuromuscular disorders. Pdf somatic mitochondrial dna mtdna mutations have been increasingly observed in primary human cancers.
The potential for mitochondrial dysfunction is increased by the presence of mitochondrial dna mtdna that, in humans, is responsible for the encoding of proteins critical for oxidative phosphorylation. Mitochondria are subcellular organelles that constitute a metabolic compartment separated from the general cytoplasm by a double layered membrane. The twinkle helicase is the main helicase in mitochondria and is the only helicase required for mtdna replication. Most dna hereditary material that is passed from parent to child is packaged within the nucleus of each cell known as nuclear dna.
Mitochondrial mutations readouts are readily compatible with singlecell measurements of cell state to provide a potent means to relate stem and progenitor cells with their differentiated progeny that. In addition, a number of other helicases with a putative role in mitochondria have been. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes. Mutations in twinkle cause a number of human disorders associated with mitochondrial dysfunction, neurodegeneration and premature ageing. Review mitochondrial dna mutations in ageing and disease. Mitochondrial dna mtdna mutations cause neurological and multisystem disease. Jci mitochondrial dna mutations in human colonic crypt stem. Pdf mitochondrial dna mutations in human cancer researchgate. Here, we study heteroplasmy in 96 multigenerational healthy families. Despite the diminutive size of the mitochondrial genome, mitochondrial dna mtdna mutations are an important cause of inherited disease. Feb 02, 2017 compared with nuclear dna, mitochondrial dna is at least 10 times more vulnerable to mutation. Request pdf mitochondrial dna mutations in human disease mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to. Mitochondrial disorders arise at any age from mutations in the nuclear dna and from defects in mtdna.
A variety of degenerative diseases involving deficiencies in mitochondrial bioenergetics have been associated with mitochondrial dna mtdna mutations. In 2008, chinnerys research team reported that pathologic mitochondrial mutations could be as high as one mutation per two hundred healthy humans. Oxidative stress increases m1dg, a major peroxidationderived dna adduct, in mitochondrial dna, nucleic acids research 2018. To investigate the role of mitochondrial dna mtdna in tumorigenesis, a temporal temperature gradient gel electrophoresis method was used to analyze the somatic mtdna mutations in breast cancer. Inherited mutations in the mitochondrial mt dna are a major cause of human disease, with approximately 1 in 5000 people affected by one of the hundreds of identified pathogenic mtdna point. We suggest that defective mitophagy promoted by mutations in mitochondrial dna can cause innate immunity disorders leading to chronification of inflammation. Although our present knowledge already indicates that mtdna mutations are an. Mitochondrial dna and disease greaves 2012 the journal. We show that mothers effectively transmit very few mitochondrial dna to their offspring. Many human genetic diseases associated with blood, brain, colon, ear, eye, heart, kidney, liver, muscle, and pancreas are caused by mutations in mitochondrial dna. Currently, more than 250 pathogenic mtdna mutations have been identified. The role of mitochondrial dna mutations in mammalian aging.
Similar oxphos defects have been shown to be present in a number of neurodegenerative conditions, including parkinsons disease, as well as in normal ageing human. Mutations in dna can result in defects of the electron transport complexes, intermediates of the tricarboxylic acid cycle and substrate transport. A number of mitochondrial dna mtdna mutations have been identified which cause familial, late onset neuromuscular degenerative diseases. Within the lifetime of an individual, mitochondrial mutations accumulate. Comprehensive scanning of somatic mitochondrial dna.
About 1 in 4,000 children in the us develop mitochondrial disease by the age of 10 years mtdna genome mutates 10 times more frequently than does nuclear dna more than 100 different. Comprehensive scanning of somatic mitochondrial dna mutations. Although our present knowledge already indicates that mtdna mutations are an important cause of disease, the true impact of these mutations on human health remains to be determined. In addition, the clinical syndromes caused by mtdna mutations have variable. The regulatory role of mitophagy in the immune response has been shown in recent studies. Jcm free fulltext possible role of mitochondrial dna.
Mitochondrial disease can also arise from nuclear gene disorders because most proteins involved in. Finally, considerable interest remains in the possibility that. Mitochondrial diseases mds include a wide range of clinical entities involving tissues that have high energy requirements such as heart, muscle, kidney and the endocrine. Mitochondrial dna mutations in human disease laura c. Mitochondrial dna mutations in human disease greaves 2006. Diseases resulting from mitochondrial dna point mutations. Map of the human mitochondrial genome depicting common genotype. Mitochondrial dna mutations in human disease, iubmb life. Techniques and pitfalls in the detection of pathogenic mitochondrial. A major impediment in our understanding of the pathophysiology of mitochondrial disorders is the complexity with which mtdna mutations are spatiotemporally distributed and managed within individual cells, tissues, and organs. Taylor mitochondrial research group, school of neurology, neurobiology and psychiatry, university. The same clinical syndrome can be caused by different genetic defects which can lie within. The human mitochondrial genome is extremely small compared with the nuclear genome, and mitochondrial genetics presents unique clinical and experimental challenges. Lineage tracing in humans enabled by mitochondrial.
To investigate the role of mitochondrial dna mtdna in tumorigenesis, a temporal temperature gradient gel electrophoresis method was used to analyze the somatic mtdna mutations. Hundreds of different point mutations and deletions of mtdna have been associated with a wide range of overlapping clini cal phenotypes. The entire mitochondrial genomes in 19 tumor samples and paired normal tissues from the same patients were amplified using 32 pairs of overlapping primers. Mitochondrial genome mitochondrial dna, mtdna lesions that unbalance bioenergetic and oxidative outputs are an important cause of human disease. Mtdna encodes essential subunits of the mitochondrial respiratory chain and defects result in impaired oxidative phosphorylation oxphos. Neutral polymorphisms are ancient, having accumulated along mtdna lineages, and thus correlate with ethnic and geographic origin. Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation oxphos defects. Pdf today there are described more than 400 point mutations and more than. We also discuss potential mechanisms for the generation of these.
Originally thought to be extremely rare, mtdna disorders are now known to affect 1 in 4,300 of the population3,4. This changed with the discovery that mutations of the mitochondrial dna could cause certain diseases. Dec 10, 2019 mitochondria frequently carry different dnaa state called heteroplasmy. Somatic mitochondrial dna mtdna mutations have been increasingly observed in primary human cancers. The figure shows a representation of the human mtdna with the location of the. Defects in mitochondrial dna mtdna mutations are the most common cause of mds in adults.
Eighty percent of mitochondrial dna codes for mitochondrial rna, and therefore most mitochondrial dna mutations lead to functional problems, which may be manifested as muscle disorders. The mitochondria are under dual controls of mitochondrial dna mtdna and nuclear dna ndna. Mitochondrial dna mtdna can cause mitochondrial diseases, which are transmitted from the mother exclusively. The replication and maintenance of mtdna is carried out by a set of. Nov 01, 2000 the development of a mouse model for heteroplasmic mtdna disease will, no doubt, herald major advances in our understanding of the tissue segregation and inheritance of mtdna mutations, and is an essential step for the development of treatments directed at the mitochondrial genome itself. Since the identification of the first human pathological mitochondrial dna mtdna mutations in 1988, significant efforts have been spent in cataloguing the vast array of. Lineage tracing in humans enabled by mitochondrial mutations. Segregation of mitochondrial dna heteroplasmy through a. It is,794 nucleotides in length and encodes 36 genes. As each cell contains many mitochondria with multiple copies of mtdna, it is. Pathogenic mitochondrial dna mutations result in mitochondrial dna disorders, which are among the most common inherited human diseases. Mitochondrial dna mutations in human disease greaves. Here we show mtdna mutations are present in primordial germ cells pgcs within healthy female human embryos. Apr 28, 2015 about 1 in 4,000 children in the us develop mitochondrial disease by the age of 10 years mtdna genome mutates 10 times more frequently than does nuclear dna more than 100 different rearrangements and about 100 different point mutations that are disease causing have been identified in mtdna.
Since their first association with human disease in 1988, more than 250 pathogenic point mutations and rearrangements of the 16. Jan 26, 2015 mitochondrial genetic disorders can be caused by changes mutations in either the mitochondrial dna or nuclear dna that lead to dysfunction of the mitochondria. We describe and compare human diseases and mouse models associated with mitochondrial genome instability. Accurate detection and quantitation of heteroplasmic. By engineering mice that rapidly accumulate mitochondrial dna mutations in the heart, we have a convenient model to study the pathogenesis of mtdna mutations. Mitochondrial mutations readouts are readily compatible with singlecell measurements of cell state to provide a potent means to relate stem and progenitor cells with their differentiated progeny that should facilitate probing the molecular circuits that underlie cellfate decisions in health and disease. Bottleneck and selection in the germline and maternal age. Mitochondrial dna mtdna defects are a relatively common cause of inherited disease and have been implicated in both ageing and cancer. A buildup of somatic mutations in mitochondrial dna has been associated with an increased risk of certain agerelated disorders such as heart disease, alzheimer disease, and parkinson disease. Isolated pgcs which have a profound reduction in mtdna. Mitochondrial genetic disorder can be inherited in a variety of manners depending on the type of condition and the location of the diseasecausing change mutation. Introduction of diseaserelated mitochondrial dna deletions into hela cells lacking mitochondrial dna results in mitochondrial dysfunction. Mitochondrial mutations and disease medical xpress.
The mitochondria contain their own mitochondrial dna mtdna. Mitochondrial dna mutations in human disease nature. It can also explain a great deal of processes related to. Both these events suggest that mtdna mutation is a fairly mitochondrial dna mutations in human colonic crypt stem cells robert w. Although it represents only a small number of genes, an. Mitochondrial dna mutations in disease and aging journal of cell. The incidence of mitochondrial diseases was higher than researchers previously had claimed. Mitochondrial genetics is different from mendelian genetics in almost every aspect, from the uniparental inheritance of disease mutations, to the presence of many copies of the genome within a single cell and the basic mechanisms that underlie replication and control of transcription table 1. Mitochondrial dna mutations in human cancer oncogene. Pdf mitochondrial genome and human mitochondrial diseases. Additionally, research suggests that the progressive accumulation of these mutations over a persons lifetime may play a role in the normal aging process.
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