Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.

Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. · pubmed

Paper

Abstract

In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.

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Research summary

The paper investigates the role of mitochondrial 6mA methylation in regulating mtDNA copy number and expression, which are crucial for oxidative phosphorylation and cellular function. The findings suggest a mechanism by which misregulation of mtDNA contributes to aging in C. elegans, addressing a potential root cause of aging rather than merely treating symptoms. This research provides important insights into the molecular mechanisms of aging and could have implications for understanding longevity, making it relevant to the field. However, while the findings are significant, they do not represent a major breakthrough that would transform the field, hence the score of 5.

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