Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function

Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA‐induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose‐, palmitate‐, and cholesterol‐enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non‐alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality. Synopsis Palmitic acid reduces the dimerization and stability of FUNDC1 in a lysophosphatidylinositol (LPI)‐dependent manner, revealing how dietary fatty acids impact on mitochondrial quality. Palmitic acid (PA), but not unsaturated oleic acid (OA), increases LPI production to impact on FUNDC1 stability and mitochondrial quality. PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows enhanced acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Graphical Abstract Palmitic acid reduces the dimerization and stability of FUNDC1 in a lysophosphatidylinositol (LPI)‐dependent manner, revealing how dietary fatty acids impact on mitochondrial quality.