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Secretory autophagy mediates mitochondria clearance in the absence of the mATG8-conjugation machinery

ABSTRACT: PINK1-Parkin mediated mitophagy, a selective form of autophagy, represents an important mechanism in mitochondrial quality control (MQC) via clearance of damaged mitochondria. Although it is well known that the conjugation of mammalian ATG8s to phosphatidylethanolamine (PE) is a key step in autophagy, its role in mitophagy remains controversial. In this study, we attempted to clarify the role of the mATG8-conjugation system in mitophagy by generating knockouts of the mATG8-conjugation machinery. Unexpectedly, we show that mitochondria could still be cleared in the absence of mATG8 lipidation, in a process that was found to be independent of lysosomal degradation. Instead, mitochondria were found to be cleared via a secretory autophagy pathway, resulting in the extracellular release of mitochondria, in a process we defined as autophagic secretion of mitochondria (ASM). Functionally, increased ASM promoted the activation of the innate immune cGAS-STING pathway in recipient cells. Overall, data from this study reveal ASM as a novel mechanism in MQC, especially when the cellular mATG8-conjugation machinery is dysfunctional.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Line Cell

DISEASE(S): Cervical Cancer

SUBMITTER: Dennis Kappei

LAB HEAD: Dennis Kappei

PROVIDER: PXD025356 | Pride | 2022-06-03

REPOSITORIES: pride

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			Action	DRS
	20210222_QPC_DK_NUS_SHM_HT_HeLa_ATG7_WTvsKO_EVs.zip	Other
	20210222_QPC_DK_NUS_SHM_HT_HeLa_ATG7_WTvsKO_EVs_for.raw	Raw
	20210222_QPC_DK_NUS_SHM_HT_HeLa_ATG7_WTvsKO_EVs_rev.raw	Raw
	checksum.txt	Txt

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Project description:Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria and mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here, we show that mtDNA damage after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, leads to an exacerbated mtDNA turnover. mtDNA removal depends on lysosomal function and requires the autophagy protein Atg5 but is independent of canonical mitophagy or autophagy. Using proximity labelling, we demonstrated that the area of influence of mitochondrial nucleoids differs upon mtDNA damage, which induces mitochondrial membrane remodelling and endosomal recruitment in close proximity to mitochondrial nucleoid sub compartments. Targeting of nucleoids is controlled by the mitochondrial transmembrane proteins ATAD3 and SAMM50, which together with the endosomal trafficking protein VPS35, orchestrate endosomal nucleoid engulfment. SAMM50 acts as a gatekeeper to avoid mtDNA release to the cytoplasm and facilitating mtDNA transfer to VPS35. Lastly, we show that stimulation of lysosomal activity by rapamycin selectively removes mtDNA deletions in vivo, without affecting mtDNA copy number. With these results, we unveil the molecular players of a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network, a process with multiple potential benefits to understand human mtDNA related diseases, either inherited, acquired or due to normal ageing.

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Secretory autophagy mediates mitochondria clearance in the absence of the mATG8-conjugation machinery

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