Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis

• Published in: Nature cell biology Vol. 25; no. 8; pp. 1157 - 1172
• Main Authors: Enkler, Ludovic, Szentgyörgyi, Viktoria, Pennauer, Mirjam, Prescianotto-Baschong, Cristina, Riezman, Isabelle, Wiesyk, Aneta, Avraham, Reut Ester, Spiess, Martin, Zalckvar, Einat, Kucharczyk, Roza, Riezman, Howard, Spang, Anne
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2023; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 14/19; 14/28; 14/34; 14/63; 631/80/642/1463; 631/80/642/2013; 631/80/642/333; 82; 82/16; 82/29; 82/80; 82/83; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Droplets; Energy metabolism; Fatty acids; Homeostasis; Life Sciences; Lipid metabolism; Lipids; Metabolism; Mitochondria; Mutants; Organelles; Oxidation; Phenotypes; Production controls; Stem Cells; Tricarboxylic acid cycle; Yeast
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-023-01180-2

Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts in the peroxisome from where β-oxidation products enter mitochondria and fuel the tricarboxylic acid cycle. Little is known about the physical and metabolic cooperation between these organelles. Here we found that expression of fatty acid transporters and of the rate-limiting enzyme involved in β-oxidation is decreased in cells expressing a hyperactive mutant of the small GTPase Arf1, leading to an accumulation of fatty acids in lipid droplets. Consequently, mitochondria became fragmented and ATP synthesis decreased. Genetic and pharmacological depletion of fatty acids phenocopied the arf1 mutant mitochondrial phenotype. Although β-oxidation occurs in both mitochondria and peroxisomes in mammals, Arf1’s role in fatty acid metabolism is conserved. Together, our results indicate that Arf1 integrates metabolism into energy production by regulating fatty acid storage and utilization, and presumably organelle contact sites. Enkler et al. show that a pool of Arf1 at lipid droplets is implicated in mitochondrial ATP production control through regulation of fatty acid metabolism and acetyl-CoA transfer to mitochondria.