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Mitochondrial dynamics and inheritance during cell division, development and disease

Key Points

  • Mitochondria are organelles with key roles in cellular metabolism. They have unique cellular dynamics to ensure their proper distribution to dividing cells and high fidelity of inheritance of their genome in a maternal mode of transmission.

  • In mammals, mitochondrial segregation during cell division seems to be primarily a passive process. Mitochondrial fusion, fission, transport, contacts with the endoplasmic reticulum and mitophagy all play a part in maintaining a homogeneous population that is spatially well distributed in the cell soma and that can thus be partitioned equally to daughter cells.

  • Mitochondrial DNA (mtDNA) inheritance from one generation to another is strongly influenced by mtDNA bottlenecks and genetic selection that occur during oogenesis and early embryonic development. Quality-control mechanisms are probably present to minimize the accumulation of pathogenic mutations, which lead to a class of diseases termed mitochondrial encephalomyopathies.

  • The depletion of paternal mitochondria during fertilization is nearly universal in metozoans, although its timing and mechanisms vary substantially between species. Proteasome-dependent degradation, mtDNA degradation and mitophagy have been implicated in this process in different organisms.

Abstract

During cell division, it is critical to properly partition functional sets of organelles to each daughter cell. The partitioning of mitochondria shares some common features with that of other organelles, particularly in the use of interactions with cytoskeletal elements to facilitate delivery to the daughter cells. However, mitochondria have unique features — including their own genome and a maternal mode of germline transmission — that place additional demands on this process. Consequently, mechanisms have evolved to regulate mitochondrial segregation during cell division, oogenesis, fertilization and tissue development, as well as to ensure the integrity of these organelles and their DNA, including fusion–fission dynamics, organelle transport, mitophagy and genetic selection of functional genomes. Defects in these processes can lead to cell and tissue pathologies.

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Figure 1: Cellular mechanisms involved in mitochondrial segregation, transport and degradation.
Figure 2: mtDNA segregation during maternal transmission and early embryogenesis.
Figure 3: Mechanisms ensuring the elimination of paternal mtDNA.

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Acknowledgements

P.M. is supported by a Baxter Postdoctoral Fellowship. Work in laboratory of D.C.C. is supported by the US National Institutes of Health grants GM062967 and GM110039, the Muscular Dystrophy Association and the Howard Hughes Medical Institute.

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Glossary

Oxidative phosphorylation

(OXPHOS). A biochemical pathway within mitochondria that generates ATP through the oxidation of nutrients.

Endosymbiotic theory

A theory postulating that genome-containing organelles, such as mitochondria and chloroplasts, are derived from bacteria that underwent endosymbiosis with ancestral eukaryotic cells.

Genetic bottlenecks

Drastic reductions in the genetic diversity of a population.

Motor proteins

Molecular motors that use ATP hydrolysis to power the movement of cargo along substrate surfaces.

Kinesins

A family of ATP-dependent molecular motors that transport cargo along microtubule filaments, usually towards the plus end.

Dyneins

A family of ATP-dependent molecular motors that transport cargo along microtubule filaments towards the minus end.

Formin proteins

A group of proteins that regulate the actin cytoskeleton and cell signalling.

Myosin

A family of ATP-dependent molecular motors that transport cargo along actin filaments.

Dynamin-related GTPases

A family of large GTP-hydrolysing enzymes related to 'classical' dynamin, which use GTP hydrolysis to mechanically remodel membranes.

mtDNA nucleoid

A punctate structure within mitochondria that contains one or more copies of the mitochondrial DNA (mtDNA) genome in complex with proteins.

Macroautophagy

The most commonly studied autophagic process, whereby cellular components are incorporated into autophagosomes and ultimately degraded or recycled through the lysosome. Macroautophagy is commonly referred to as simply 'autophagy'.

Autophagosomes

Double-membrane structures that engulf cellular components for delivery to lysosomes.

Lysosomes

Organelles that degrade cellular components using acid hydrolases.

Cytoplasmic hybrid (cybrid) cells

Hybrid cells created by the fusion of a cell with an enucleated second cell, thereby combining the nucleus and mitochondria from two distinct cells.

Heteroplasmic

A state in which more than one haplotype of mitochondrial DNA exists in a cell or an organism.

Homoplasmy

A state in which a single haplotype of mitochondrial DNA exists in a cell or an organism.

Genetic drift

A change in the allele or haplotype frequencies within a population owing to stochastic forces.

Purifying selection

A mode of natural selection in which detrimental genetic variants are selected against.

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Mishra, P., Chan, D. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15, 634–646 (2014). https://doi.org/10.1038/nrm3877

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