Yunki Lim¹, Brandon Berry², Stephanie Viteri¹, Matthew McCall³, Eun Chan Park⁴, Christopher Rongo⁴, Paul S Brookes^2,5, Keith Nehrke^1,2,*

¹Medicine and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY.
²Pharmacology and Physiology and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY.
³Biostatistics and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY.
⁴Waksman Institute/Rutgers University, Piscataway, NJ.
⁵Anesthesiology, and Perioperative Medicine Departments, School of Medicine and Dentistry, University of Rochester Medical Center , Rochester, NY.

^*Corresponding author

Mitochondrial quality control (MQC) balances organelle adaptation and elimination, and mechanistic crosstalk between the underlying molecular processes affects subsequent stress outcomes. FUNDC1 (FUN14 domain containing 1) is a mammalian mitophagy receptor that responds to hypoxia-reoxygenation (HR) stress. Here, we provide evidence that FNDC-1 is the C. elegans ortholog of FUNDC1, and that its loss protects against injury in a worm model of HR. This protection depends upon ATFS-1, a transcription factor that is central to the mitochondrial unfolded protein response (UPRmt). Global mRNA and metabolite profiling suggest that atfs-1-dependent stress responses and metabolic remodeling occur in response to the loss of fndc-1. These data support a role for FNDC-1 in non-hypoxic MQC, and further suggest that these changes are prophylactic in relation to subsequent HR. Our results highlight functional coordination between mitochondrial adaptation and elimination that organizes stress responses and metabolic rewiring to protect against HR injury.