Resolving the enigma of the clonal expansion of mtDNA deletions

TY - JOUR

T1 - Resolving the enigma of the clonal expansion of mtDNA deletions

AU - Kowald, Axel

AU - Kirkwood, Thomas B.L.

PY - 2018

Y1 - 2018

N2 - Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging.

AB - Mitochondria are cell organelles that are special since they contain their own genetic material in the form of mitochondrial DNA (mtDNA). Damage and mutations of mtDNA are not only involved in several inherited human diseases but are also widely thought to play an important role during aging. In both cases, point mutations or large deletions accumulate inside cells, leading to functional impairment once a certain threshold has been surpassed. In most cases, it is a single type of mutant that clonally expands and out-competes the wild type mtDNA, with different mutant molecules being amplified in different cells. The challenge is to explain where the selection advantage for the accumulation comes from, why such a large range of different deletions seem to possess this advantage, and how this process can scale to species with different lifespans such as those of rats and man. From this perspective, we provide an overview of current ideas, present an update of our own proposal, and discuss the wider relevance of the phenomenon for aging.

KW - Aging

KW - Mitochondrial deletion mutants

KW - Model of clonal expansion

U2 - 10.3390/genes9030126

DO - 10.3390/genes9030126

M3 - Journal article

C2 - 29495484

AN - SCOPUS:85042750862

SN - 2073-4425

VL - 9

JO - Genes

JF - Genes

IS - 3

M1 - 126

ER -