Lysosomal uptake of mtDNA mitigates heteroplasmy

Abstract

Mitochondrial DNA is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress the mitochondrial genome transfers to endosomes where it is degraded. Here, using proximity proteomics we found that mtDNA replication stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria association with lysosomal and vesicle-associated proteins, such as the GTPase RAB10 and the retromer. We found that upon mtDNA replication stress, RAB10 enhances mitochondrial fragmentation and relocates from the ER to lysosomes containing mtDNA. The retromer enhances and coordinates the expulsion of mitochondrial matrix components through mitochondrial-derived vesicles, and mtDNA with direct transfer to lysosomes. Using aDrosophilamodel carrying a long deletion on the mtDNA (ΔmtDNA), we evaluatedin vivothe role of the retromer in mtDNA extraction and turnover in the larval epidermis. The presence of ΔmtDNA elicits the activation of a specific transcriptome profile related to counteract mitochondrial damage. Expression of the retromer componentVps35is sufficient to restore mtDNA homoplasmy and mitochondrial defects associated with ΔmtDNA. Our data reveal novel regulators involved in the specific elimination of mtDNA. We demonstrate that modulation of the retromerin vivois a successful mechanism to restore mitochondrial function associated with mtDNA damage.