Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Ayesha Sen, Sebastian Kallabis, Felix Gaedke, Christian Jüngst, Julia Boix, Julian Nüchel, Kanjanamas Maliphol, Julia Hofmann, Astrid C. Schauss, Marcus Krüger, Rudolf J. Wiesner and David Pla-Martín ()
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Ayesha Sen: Faculty of Medicine and University Hospital Cologne, University of Cologne
Sebastian Kallabis: University of Cologne
Felix Gaedke: University of Cologne
Christian Jüngst: University of Cologne
Julia Boix: Faculty of Medicine and University Hospital Cologne, University of Cologne
Julian Nüchel: Faculty of Medicine and University Hospital Cologne, University of Cologne
Kanjanamas Maliphol: Faculty of Medicine and University Hospital Cologne, University of Cologne
Julia Hofmann: Faculty of Medicine and University Hospital Cologne, University of Cologne
Astrid C. Schauss: University of Cologne
Marcus Krüger: University of Cologne
Rudolf J. Wiesner: Faculty of Medicine and University Hospital Cologne, University of Cologne
David Pla-Martín: Faculty of Medicine and University Hospital Cologne, University of Cologne

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.

Date: 2022
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DOI: 10.1038/s41467-022-34205-9

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