Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination

Abstract

Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them toward elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.

Keywords: Mitophagy; endosomes; mtDNA.

Figure 1.

Proposed model for mitochondrial nucleoid elimination upon mtDNA damage. Disruption of the ATAD3-SAMM50 axis initiates mitochondrial nucleoid extraction. Upon BAK1 clustering, mtDNA is transferred to endosomes in a SAMM50-dependent manner. VPS35 mediates maturation of these vesicles to late autophagy organelles or multivesicular bodies (MVB). Nucleoid elimination avoids the activation of the CGAS-STING1 pathway activated by cytoplasmic mtDNA or an exacerbated mitophagy, observed in SAMM50 knockdown cells and Vps35 knockout, respectively. Model generated with biorender.com.