biostudies-literatureMondal MDeutsche Forschungsgemeinschaft (German Research Foundation)Helmholtz Association10817https://www.ebi.ac.uk/biostudies/studies/S-EPMC12669733biostudies-literatureUnknown16(1)Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRKNature communicationsDietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.PMC12669733core funding541647076Jussila BRiemer JMondal MMenegatou IMNicotera PScifo ESchreiber LCiliberti REBano DKierszniowska SEhninger DHopkins CEZeisler-Diehl VWischhof LAbbariki TNJackson JfalseDietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK2025-01-01T00:00:00Z2025 Dec2026-06-05T21:49:46.404Z2026-05-22T03:16:16.585ZS-EPMC126697334132638510.1038/s41467-025-66900-8