Dietary 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 LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
Authors
- Sylwia Kierszniowska (ORCID: https://orcid.org/0000-0002-4736-9222)
- Lena Wischhof (ORCID: https://orcid.org/0000-0002-2203-408X)
- Mrityunjoy Mondal (ORCID: https://orcid.org/0000-0003-2973-4633)
- Jan Riemer (ORCID: https://orcid.org/0000-0002-7574-8457)
- Viktoria V. Zeisler‐Diehl (ORCID: https://orcid.org/0000-0001-7050-9716)
- Benjamin Jussila (ORCID: https://orcid.org/0000-0001-9764-0482)
- Lukas Schreiber (ORCID: https://orcid.org/0000-0001-7003-9929)
- Daniele Bano (ORCID: https://orcid.org/0000-0002-9617-5504)
- Enzo Scifo (ORCID: https://orcid.org/0000-0002-0450-6573)
- Christopher E. Hopkins (ORCID: https://orcid.org/0000-0002-6981-6329)
- Dan Ehninger (ORCID: https://orcid.org/0000-0001-7464-1335)
- Tannaz Norizadeh Abbariki (ORCID: https://orcid.org/0009-0003-0980-8639)
- Pierluigi Nicotera (ORCID: https://orcid.org/0000-0003-1175-7466)
- Joshua Jackson (ORCID: https://orcid.org/0000-0002-3515-5593)
- Rossella Erminia Ciliberti (ORCID: https://orcid.org/0009-0007-3408-7182)
- Ioanna-Maria Menegatou
Institutions
- University of Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- Foundation Center (US)
- Urology Foundation (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Mahle (Austria) (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1038/s41467-025-66900-8
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- HORIZON EUROPE Framework Programme
- H2020 Marie Skłodowska-Curie Actions