The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease

Key Points

  • Mitochondria contain their own genome, which is maternally inherited and codes for polypeptides forming the mitochondrial respiratory chain. Mitochondrial DNA (mtDNA) has a structure and code different from those of the nuclear genome.

  • mtDNA mutations contribute to human disease across a range of severity, from rare, highly penetrant mutations causal for monogenic disorders that often affect the nervous system, muscles, heart and endocrine organs, to mutations that have a milder contribution to common complex traits and late-onset disorders.

  • Many healthy humans harbour low levels (<1%) of mtDNA point mutations, including both inherited and acquired mutations. An increased burden of acquired mutations can contribute to late-onset diseases.

  • Studies in model organisms are beginning to provide insights into the mechanisms by which the acquisition of new mtDNA mutations is suppressed, particularly in the germ line.


Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk of late-onset disorders.

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Figure 1: mtDNA heteroplasmy and the threshold effect.
Figure 2: New technologies to analyse mtDNA.
Figure 3: mtDNA heteroplasmy can change throughout the lifetime of an individual.
Figure 4: Models for the mtDNA genetic bottleneck.
Figure 5: Human population migrations and major mtDNA haplogroups.


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J.B.S. is supported by the Max Planck Society and a project grant from the United Mitochondrial Disease Foundation. P.F.C. is an honorary consultant neurologist at Newcastle upon Tyne Foundation Hospitals UK National Health Service (NHS) Foundation Trust, a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK National Institute for Health Research (NIHR) senior investigator. P.F.C. receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the UK Medical Research Council Centre for Translational Muscle Disease research (G0601943), the European Union FP7 (Seventh Framework Programme for Research and Technological Development) TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration) consortium, and the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health.

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Correspondence to Patrick F. Chinnery.

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A major phylum of Gram-negative bacteria.

Iron–sulfur clusters

Associated iron and sulfur molecules forming part of an iron–sulfur protein.


A situation in which all the mitochondrial DNA molecules within a cell or organism are identical.


A mixture of wild-type and mutant mitochondrial DNA within the cell. The percentage of mtDNA containing mutations can vary from 1% to 99%.


A cytoplasmic hybrid cell line made by fusing a whole cell with a cytoplast and usually used as a cellular model system to study the effects of mitochondrial DNA variants or mutations on the same nuclear genetic background.

Warburg effect

The shift from aerobic to anaerobic (glycolytic) metabolism that characterizes rapidly dividing cancer cell lineages.

Nuclear mitochondrial DNA sequences

(NUMTs). Pseudogene sequences in nuclear DNA that are derived from mitochondrial DNA.

Vegetative segregation

Changes in heteroplasmy that occur owing to the unequal partitioning of different mitochondrial genotypes during cell division.

Relaxed replication

DNA replication that occurs continuously throughout the cell cycle and is independent of nuclear division, as with mitochondrial DNA.

Replicative advantage

A situation in which one molecule is preferentially copied over another.


Groups of similar haplotypes (groups of genes) that share several polymorphisms. Single-nucleotide variants acquired during human history have subdivided the mitochondrial DNA phylogeny into several major haplogroups, typically present at >5% in the population.


A restriction in the number of molecules (for example, mitochondrial DNA) or groups of molecules arranged in segregating units.


Mutations of the same nucleotide at the same genomic position arising by two (or more) independent mutations.

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Stewart, J., Chinnery, P. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet 16, 530–542 (2015).

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