Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans

Area of Science:

• Mitochondrial biology
• Genetics
• Cellular homeostasis

Background:

• Mutant mitochondrial genomes (mtDNA) can act as selfish genetic elements.
• These elements persist in heteroplasmy despite potential metabolic harm.
• Understanding the regulation of selfish mtDNA dynamics is crucial.

Purpose of the Study:

• To investigate the regulatory mechanisms governing selfish mtDNA dynamics.
• To characterize the role of the mitochondrial unfolded protein response (UPR(mt)) in selfish mtDNA propagation.
• To determine how mtDNA copy-number control influences selfish mtDNA frequency.

Main Methods:

• Establishing the uaDf5 deletion-bearing mtDNA variant as a selfish genome in Caenorhabditis elegans.
• Quantifying mtDNA replication rates in the presence of uaDf5.
• Assessing the impact of UPR(mt) activation and inhibition on uaDf5 frequency.
• Investigating the effect of UPR(mt) on mitophagy of uaDf5.

Main Results:

• The uaDf5 mutant mtDNA replicates alongside wild-type mtDNA, suggesting exploitation of homeostatic copy-number control.
• uaDf5 animals exhibit activation of the mitochondrial unfolded protein response (UPR(mt)).
• Loss of UPR(mt) decreases uaDf5 frequency, while its activation increases uaDf5 levels.
• UPR(mt) activation confers protection to uaDf5 against mitophagy.

Conclusions:

• mtDNA copy-number control is exploited by selfish mtDNA variants like uaDf5 to achieve high frequency.
• UPR(mt) activation is a key mechanism that promotes the persistence of selfish mtDNA by preventing mitophagy.
• mtDNA copy-number control and UPR(mt) are critical homeostatic mechanisms regulating selfish mitochondrial genome dynamics.