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Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans
Journal article   Open access   Peer reviewed

Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans

Julien Goldstick, Diego Compte, Chun-Ling Sun, Alison E Ritter and C Michael Crowder
The FASEB journal, v 40(13), e72089
15 Jul 2026
DOI: https://doi.org/10.1096/fj.202601561R
PMID: 42366871
url
https://doi.org/10.1096/fj.202601561RView
Published, Version of Record (VoR) Open

Abstract

Animals Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans - physiology Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Caenorhabditis elegans Proteins - physiology Cell Death Dynamins - genetics Dynamins - metabolism Hypoxia - metabolism Mitochondria - metabolism Mitochondrial Dynamics Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Mutation
Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measured the effect of hypoxia on mitochondrial morphology in a Caenorhabditis elegans Raptor mutant resistant to hypoxic death and in mutants with disrupted mitochondrial fission and fusion. The Raptor loss-of-function mutant reduced hypoxia-induced mitochondrial fragmentation and death. However, forcing mitochondrial fragmentation prior to hypoxia by combining the Raptor mutation with a loss-of-function mutation in mitofusin did not increase hypoxic death. A loss-of-function mutation in drp-1, which is required for mitochondrial fission, did not block hypoxia-induced mitochondrial fragmentation nor enhance Raptor hypoxia resistance; rather, drp-1(lf) was surprisingly mildly hypoxia resistant and partially suppressed the high-level hypoxia resistance of the Raptor mutant. Likewise, loss of DRP-1 function interacted synthetically with the Raptor(lf) mutant to produce tangled mitochondria, demonstrating a role of Raptor in maintenance of the mitochondrial network. Vitamin B12 supplementation and feeding with a bacterial strain replete in vitamin B12 mitigated hypoxia-induced mitochondrial fragmentation. Our results demonstrate that fragmented mitochondria do not necessarily promote hypoxic cell death, and hypoxia-induced mitochondrial fragmentation is mechanistically distinct from physiological mitochondrial fission.

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