Universität zu Köln

Sen, Ayesha, Kallabis, Sebastian, Gaedke, Felix, Juengst, Christian, Boix, Julia, Nuechel, Julian, Maliphol, Kanjanamas, Hofmann, Julia, Schauss, Astrid C., Krueger, Marcus, Wiesner, Rudolf J. and Pla-Martin, David (2022). Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

Full text not available from this repository.

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. Mitochondrial quality control mechanisms prevent damage accumulation, including in mitochondrial DNA (mtDNA). Here, Sen et al. show that altered mtDNA elicits local rearrangements in mitochondrial membrane potential and cristae structure, with mtDNA eliminated through VPS35 endosomes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sen, Ayesha UNSPECIFIED UNSPECIFIED UNSPECIFIED Kallabis, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaedke, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Juengst, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Boix, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuechel, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Maliphol, Kanjanamas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesner, Rudolf J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pla-Martin, David UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-657352
DOI:	10.1038/s41467-022-34205-9
Journal or Publication Title:	Nat. Commun.
Volume:	13
Number:	1
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language QUALITY-CONTROL; SKELETAL-MUSCLE; DNA; MUTATIONS; MITOPHAGY; DELETIONS; STABILITY; AUTOPHAGY; TRANSPORT; PATHWAY Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/65735