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Human mitochondrial DNA: roles of inherited and somatic mutations

Key Points

  • Mitochondrial diseases are among the most common genetic disorders. They can result from mutations in the mitochondrial genome or nuclear genome.

  • The mitochondrial genome needs to be understood in terms of population genetics, rather than Mendelian genetics; this makes it particularly challenging to understand mitochondrial diseases.

  • Mutations in mitochondrial DNA (mtDNA) accumulate over the lifetime of an individual and are now implicated in ageing and neurodegeneration.

  • There is current interest in exploring possible roles of mitochondrial genetic variation in susceptibility to complex diseases, but the evidence remains uncertain at present.

  • The literature documenting the accumulation of mtDNA mutations in tumours needs to be interpreted with caution.

Abstract

Mutations in the human mitochondrial genome are known to cause an array of diverse disorders, most of which are maternally inherited, and all of which are associated with defects in oxidative energy metabolism. It is now emerging that somatic mutations in mitochondrial DNA (mtDNA) are also linked to other complex traits, including neurodegenerative diseases, ageing and cancer. Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis.

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Figure 1: Mitochondrial DNA and the human respiratory chain/oxidative phosphorylation system.
Figure 2: Example of the potential to amplify inadvertently a nucleus-embedded mitochondrial sequence.

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Acknowledgements

The authors were supported by grants from the US National Institutes of Health (HD32062), the US Department of Defense (W911NF-12-1-0159), the Muscular Dystrophy Association, the Ellison Medical Foundation, the Alzheimer Drug Discovery Foundation and the Marriott Mitochondrial Disorder Clinical Research Fund.

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Correspondence to Eric A. Schon.

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Eric A. Schon is a paid consultant to Mitomics, Inc., which is developing tests to diagnose cancer on the basis of the presence of mutations in tumour mitochondrial DNA (mtDNA). Salvatore DiMauro and Michio Hirano declare no competing financial interests.

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Glossary

Microarray-based sequencing

DNA sequencing based on the ability of the target DNA to hybridize to an ordered set of defined oligonucleotides immobilized on a chip.

Monochromosomal transfer

Typically, the transfer of individual human chromosomes (or parts of chromosomes) to rodent cells in order to identify and map human genes responsible for disease.

Mitodynamics

The morphological properties of mitochondria (for example, fusion, fission, distribution, anchorage, positioning). These properties can change both in space and in time within cells.

Primary pathogenic mtDNA mutations

Mutations that can compromise OXPHOS function and cause disease. They arise in mtDNA through processes such as random errors during normal mtDNA replication.

Nystagmus

An involuntary, quick, rhythmic movement of the eyeball, which can be horizontal, vertical or rotary.

Hemiplegia

Paralysis of the left or right side of the body owing to a brain lesion affecting motor pathways.

Strongly SDH-positive vessels

(SSVs). Abnormal, massive accumulation of mitochondria in blood vessels, as visualized by enzyme histochemistry to detect the activity of succinate dehydrogenase (SDH; complex II of the respiratory chain).

Heteroplasmic

A term that describes the presence of two or more mtDNA genotypes within a cell, tissue or organism.

Lactic acidosis

The abnormal accumulation of lactic acid causing lower pH in blood in a resting individual (that is, not during or immediately after exercise), which is seen in many patients with mitochondrial disease.

Myoclonus

Involuntary jerky movement of an area of the body (usually a limb).

Mitochondrial transmembrane potential

(Δψm). This is the electrical potential generated across the mitochondrial inner membrane due to differences in the distribution of ions (for example, H+, Ca2+, Na+, K+ and ionized ATP species) between the matrix and the intermembrane space.

Secondary mtDNA mutations

Mutations that can compromise OXPHOS function and cause disease and that arise in mtDNA owing to a mutation in the nuclear genome that compromises mtDNA integrity (for example, a mutation in mitochondrial DNA polymerase-γ causing systemic errors in mtDNA replication).

Homoplasmic

A term that describes the presence of a single mtDNA genotype within a cell, tissue, or organism.

Aerobic glycolysis

The conversion of glucose to lactate (and the production of ATP by substrate level phosphorylation) even in the presence of oxygen, especially in tumours.

Double minute DNAs

(dmDNAs). Tiny fragments of extrachromosomal nuclear DNA found in many tumours, derived from the amplification of small regions of chromosomal DNA.

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Schon, E., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 13, 878–890 (2012). https://doi.org/10.1038/nrg3275

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