Mechanisms behind programmed mtDNA deletions and the restoration of intact mtDNA

Mitochondrial impairment is strongly associated with aging and age-related diseases and mitochondrial DNA (mtDNA) deletions explain much of this impairment. mtDNA deletions have long been thought of as accidents but wer have shown d that the defense against oxidative stress involves genetically programmed mtDNA deletions that impair OXPHOS and reduce intramitochondrial O2·-  production, thereby facilitating oxidative stress adaptation.We here seek to understand how signal transmission through the retrograde signaling pathway leads to the emergence of mtDNA deletions that defend cells against oxidative stress.

We will also explore how retrograde pathway activation of transcriptional targets in the nuclear genome results in mtDNA deletions.

Next, we will probe how cells restore the copy numbers of intact mtDNA molecules and recover their full respiratory capacity after the oxidative stress.

We will test both the importance of cellular inactivation of the retrograde pathway in this recovery and the roles that targeted mitophagy or mitochondrial inheritance play.Cellular control over mtDNA deletions, and thereby over the rate of adaptive evolution, and the existence of a previously unknown defense layer against oxidative stress, should all be of interest to a broad audience in genetics, cell and evolutionary biology.

Ultimately, our findings may prove to be of etiological and therapeutic importance for how we view and manage aging and age-related disease.