Synergistic Roles of FAHD‐1 and PYC‐1 in Mitochondrial Function, Behavior, and Longevity in C. elegans

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ABSTRACTMitochondrial metabolism plays a central role in organismal physiology and aging. In Caenorhabditis elegans, FAHD‐1 (oxaloacetate decarboxylase) and PYC‐1 (pyruvate carboxylase) catalyze opposing reactions that influence oxaloacetate homeostasis within the tricarboxylic acid cycle. To dissect their functional interplay, we analyzed single‐ and double‐knockout strains generated by CRISPR/Cas9 alongside the classical allele. Fahd‐1 mutants exhibit impaired mitochondrial respiration, reduced motility, and early egg‐laying onset, whereas pyc‐1 mutants display increased locomotion and enhanced metabolic flexibility. Paradoxically, although each single mutantion extended lifespan, combining them restored wild‐type lifespan and partially normalized respiratory function, suggesting a compensatory interaction. These findings establish FAHD‐1 and PYC‐1 as antagonistic mitochondrial enzymes whose balance governs locomotion, reproduction, and lifespan in C. elegans, providing a conceptual framework for conserved links between mitochondrial metabolism and aging.