206 - The Mitophagy Receptor FUNDC-1 Contributes to Hypoxia-Reoxygenation Stress in C. elegans

Abstract

Mitochondrial are central to hypoxia-reoxygenation (H/R) injury in both mammals and the nematode C. elegans and mitochondrial quality control (MQC) mechanisms including the mitochondrial unfolded protein response (UPR mt ), the production of anti-oxidants, and mitophagy are important for adapting to H/R stress. FUNDC1 (FUN14 domain containing 1) is a hypoxia-induced mitophagy mediator that has been characterized in mammalian cells. FUNDC1 is located on the mitochondrial outer-membrane and directly binds to LC3 and Drp1. However, the contribution of FUNDC1 to MQC and its interaction with other signaling pathways is currently unknown. We have identified a putative C. elegans FUNDC1 ortholog T06D8.7 (here after referred to as fundc-1 ) and begun to analyze its role in MQC during H/R. Fundc-1 is in an operon together with three other genes that are involved in mitochondria or proteasome function. Here, we demonstrate that transcription of fundc-1 is activated by hypoxia through HIF1 binding sites in both intragenic and operon promoters. We have generated fundc-1 mutant worms using CRISPR-Cas9 mutagenesis and find that loss-of-function worms are protected against hypoxic injury and death. Atfs-1 codes for a central regulator of UPR mt that we have recently shown is both necessary and sufficient to protect against H/R injury in C. elegans. Atfs-1 loss-of-function suppresses the T06D8.7 hypoxic-protected phenotype. This suggests that disrupting mitophagy elicits an UPR mt and subsequent adaptation to hypoxia. Use of the C. elegans model will facilitate dissecting interactions between fundc-1 and other hypoxia-relevant signaling pathways implicated in MQC.