Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.

Haixin Zhang,Patrick F Chinnery,James B Stewart,Nick Jones,Carlo Viscomi,Mikael G Pezet,Mitinori Saitou,Juvid Aryaman,Wei Wei,Marcos R Chiaratti,Carolina H Macabelli,Claudia Calabrese,Florian Klimm,Stephen P Burr,Marco Esposito

doi:10.1126/sciadv.abi5657

Abstract

Heteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild-type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders.

Highlights

Over 100 different single-nucleotide variants of the 16.6-kilobase mitochondrial genome cause mitochondrial disorders affecting ~1 in 8000 humans [1, 2], but a very small number of independently recurring mutations present in the clinic, with m.3243A>G being overwhelmingly the most common, accounting for 80% of adults with a pathogenic heteroplasmic mitochondrial DNA (mtDNA) mutation [3]
To explore potential mechanisms responsible for the preferential transmission of mutant mtDNA, we studied the m.5024C>T tRNAAla mutation in mice [12, 13], which compromises oxidative phosphoryl ation when >90% of molecules are affected in cardiomyocytes and
Adv. 7, eabi5657 (2021) 8 December 2021 corresponds to the known m.5650G>A pathogenic mtDNA mutation in humans [14, 15]

Summary

Introduction

Over 100 different single-nucleotide variants of the 16.6-kilobase (kb) mitochondrial genome (mtDNA) cause mitochondrial disorders affecting ~1 in 8000 humans [1, 2], but a very small number of independently recurring mutations present in the clinic, with m.3243A>G being overwhelmingly the most common, accounting for 80% of adults with a pathogenic heteroplasmic mtDNA mutation [3]. The signature of selection has been seen in the offspring of several species [8,9,10,11], including humans [4], typically limiting the inheritance of deleterious mutations that compromise oxidative phosphorylation. This raises the question—If selection “purifies” the mtDNA population during germline development, how do pathogenic mtDNA mutations ever reach levels that cause human diseases?

Methods

Results

Conclusion