Hsp90 and its mitochondrial homologue TRAP-1 independently regulate hypoxia adaptations in Caenorhabditis elegans

Mitochondrial adaptations to various environmental cues contribute to cellular and organismal adaptations across multiple model organisms. Due to increased complexity, a direct connection between mitochondrial integrity and oxygen fluctuations, and survival fitness was not demonstrated. Here, using C. elegans as a model system, we studied the role of HIF-1, Hsp90, and TRAP-1 in mitochondrial adaptations during chemical hypoxia. We show that Hsp90^mt (Hsp90 mutant) but not HIF-1^mt (HIF-1 mutant) affects hypoxia adaptation in nematodes. TRAP-1^KD (TRAP-1 knockdown) interfered with the survival and fecundity of worms. Compared to Hsp90^mt, TRAP-1^KD has induced a significant decrease in mitochondrial integrity and oxygen consumption rate. The complex I inhibitor rotenone did not affect ATP levels in Hsp90^mt worms. However, ATP levels were decreased in TRAP-1^KD worms under similar conditions. The glucose restriction has reduced, and glucose supplementation has increased the survival rate in Hsp90^mt worms. Neither glucose restriction nor glucose supplementation has significantly affected the survival of TRAP-1^KD worms in response to hypoxia. However, TRAP-1 inhibition using a nanocarrier drug has dramatically reduced the survival rate in response to hypoxia. Our results suggest that Hsp90 and TRAP-1 independently regulate hypoxia adaptations and metabolic plasticity in C. elegans. Considering the emerging roles of TRAP-1 in altered energy metabolism and cellular adaptations, our findings gain importance.