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The organization and inheritance of the mitochondrial genome

Nature Reviews Genetics volume 6, pages 815–825 (2005)Cite this article

Key Points

  • Mitochondrial DNA (mtDNA) is generally packaged into nucleoids, the heritable units of mtDNA, by the Abf2/TFAM (transcription factor A, mitochondrial)-family of HMG (high mobility group)-box proteins, which are conserved from yeast to humans. However, recent studies have also revealed several metabolic enzymes that are associated with mtDNA in both yeast and vertebrates.

  • The metabolic proteins that are found in yeast mitochondrial nucleoids can substitute for Abf2 in mtDNA packaging and protection when their expression is increased in response to metabolic cues. These findings indicate that the structural organization of mitochondrial nucleoids is subject to remodelling by these metabolically regulated bifunctional proteins.

  • Mitochondrial nucleoid (mt-nucleoid) division can be directly observed by microscopy. The yeast Hsp60 (heat shock protein 60) chaperonin is a bifunctional protein that is involved in this process.

  • Proteins that are involved in mtDNA recombination affect mt-nucleoid number and mtDNA transmissibility. Genes that are involved in mtDNA concatemerization could accelerate the establishment of homoplasmy in dividing cells.

  • Extensive mitochondrial fission leads to the production of mitochondria that are devoid of mt-nucleoids, and transmission of those mitochondria to progeny cells can eventually lead to the loss of mtDNA. Yeast mitochondria are equipped with a membrane-spanning device that physically links mt-nucleoids to the actin cytoskeleton, which provides a mechanism for coupling mitochondrial movement and mtDNA segregation during cell division.

  • mtDNA mutations have causative roles in neuromuscular diseases and cellular ageing. Studies of the organization and inheritance of mt-nucleoids could help us to understand how the mitochondrial genetic system is affected under these conditions.

Abstract

Mitochondrial DNA (mtDNA) encodes essential components of the cellular energy-producing apparatus, and lesions in mtDNA and mitochondrial dysfunction contribute to numerous human diseases. Understanding mtDNA organization and inheritance is therefore an important goal. Recent studies have revealed that mitochondria use diverse metabolic enzymes to organize and protect mtDNA, drive the segregation of the organellar genome, and couple the inheritance of mtDNA with cellular metabolism. In addition, components of a membrane-associated mtDNA segregation apparatus that might link mtDNA transmission to mitochondrial movements are beginning to be identified. These findings provide new insights into the mechanisms of mtDNA maintenance and inheritance.

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Figure 1: Cytological visualization of yeast mitochondrial nucleoids.
Figure 2: A model for the metabolic remodelling of mitochondrial nucleoids in yeast.
Figure 3: Understanding the mechanism of mitochondrial nucleoid segregation.
Figure 4: A model of the yeast mitochondrial nucleoid segregation apparatus.

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Acknowledgements

X.J.C. is supported by the US National Institutes of Health (NIH) and American Heart Association and R.A.B is supported by the NIH and The Robert A. Welch Foundation. We are grateful to our colleagues for their helpful discussions and a critical reading of the manuscript.

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  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, 75390-9148, Texas, USA

    Xin Jie Chen & Ronald A. Butow

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Correspondence to Ronald A. Butow.

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DATABASES

Entrez

Entrez

Abf2

ACO1

Cce1

Fzo1

ILV5

MHR1

Mdm10

Mdm12

Mdm31

Mdm32

Mgm101

Mmm1

mttfa-A

Ugo1

MedlinePlus

MedlinePlus

cisplatin

Swiss-Prot

Swiss-Prot

TFAM

FURTHER INFORMATION

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Glossary

HIGH MOBILITY GROUP (HMG) PROTEINS

A family of non-histone proteins that contain DNA-binding HMG-box domains.

ATOMIC FORCE MICROSCOPY

A method that is used to image materials at the atomic level.

PETITE MUTANTS

Respiratory-deficient mutants. These either contain a highly repeated, random fragment of the wild-type mitochondrial genome (ρ−) or completely lack mtDNA (ρ°).

FOOTPRINT ANALYSIS

A technique for identifying sites where proteins bind to DNA at a single-nucleotide resolution.

REDUCTIONAL RECOMBINATION

Recombination within the highly repeated sequences of ρ−-petite genomes, which produces shorter mtDNA molecules with a reduced number of repeat units.

KREBS CYCLE

Also known as the tricarboxylic acid (or TCA) cycle. A metabolic pathway in mitochondria that breaks down the products of carbohydrate, fat and protein metabolism into carbon dioxide and water to generate energy. It also provides precursors for other compounds, such as certain amino acids.

CHAPERONIN

A protein complex that is required for correct protein folding.

DECONVOLUTION MICROSCOPY

Microscopy using computer image-processing techniques to reconstruct cross-sectional images from several focal planes, which yields high-resolution images.

ROLLING-CIRCLE REPLICATION

A form of DNA replication in which a circular DNA molecule produces linear daughter molecules.

HOMOPLASMY

The state of the mitochondrial genetic system in which all copies of the mitochondrial genome within a cell are identical.

HETEROPLASMY

The state of the mitochondrial genetic system in which a cell contains mitochondrial genomes that are genetically different.

FLUORESCENCE IN SITU HYBRIDIZATION

A microscopic technique that uses fluorescently tagged DNA probes to detect the cytological localization of specific DNAs by in situ hybridization.

PRE-PROTEIN TRANSLOCASE

A complex of proteins that function in the import of nuclear-encoded mitochondrial proteins that were synthesized on cytoplasmic ribosomes.

REPLISOME

A DNA-replicating structure that is located at the replication fork, which consists of DNA-replication enzymes and associated proteins.

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Chen, X., Butow, R. The organization and inheritance of the mitochondrial genome. Nat Rev Genet 6, 815–825 (2005). https://doi.org/10.1038/nrg1708

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