Mutations of mtDNA - inheriting without perishing

Introduction

Mutations of mtDNA cause mitochondrial diseases and are heavily implicated in the pathophysiology of age-associated diseases and ageing. Low levels of mtDNA mutations are universally present in somatic tissues of all humans, and mtDNA mutations have been reported to contribute to age-associated diseases.

Mechanisms of Mutation Accumulation

Somatic mutations of mtDNA often arise during the massive mtDNA replication in embryogenesis and can accumulate postnatally by clonal expansion. Furthermore, ongoing mtDNA replication during adult life also contributes to the burden of mtDNA mutations in mammalian somatic tissues.

Transmission of mtDNA

Mammalian mtDNA is maternally transmitted without germline recombination, and this asexual mode of transmission should theoretically lead to a mutational meltdown over generations, the so-called Muller ratchet.

Counteracting Mechanisms

At least two poorly understood mechanisms in the maternal germline counteract the transmission of mutated mtDNA from mother to offspring:

1. Bottleneck Mechanism: This ensures that only a fraction of the pool of mtDNA variation in the mother is transmitted to the offspring.
2. Purifying Selection: This functionally tests mtDNA and decreases the transmission of mutations.

Research Proposal

In this proposal, we will use powerful mouse models and completely new experimental strategies to study how mammalian mtDNA mutations are inherited and how somatic mtDNA mutations contribute to age-associated disease and ageing.

Clinical Implications

Maternally inherited pathogenic mtDNA mutations often cause life-threatening incurable diseases with failure of multiple organs in humans. Unfortunately, the principles for inheritance of pathogenic mtDNA mutations are often unclear, and the knowledge generated in this proposal will give a better basis for genetic counselling.

Scientific Interest

Furthermore, the mechanisms counteracting a mutational meltdown of the non-recombining, maternally transmitted mtDNA is a central question in biology of great basic scientific interest.