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Saturated fatty acids increase LPI to reduce FUNDC1 dimerization and stability and mitochondrial function.
Linbo Chen1, Qianping Zhang1, Yuanyuan Meng1
1State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China.
EMBO Reports
|February 27, 2023
Summary
Saturated fatty acids increase lysophosphatidylinositol (LPI), destabilizing the FUNDC1 mitophagy receptor and impairing mitochondrial quality. Unsaturated fatty acids counteract these effects, revealing a key lipid-mitochondria signaling pathway.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Disorders
Background:
- Ectopic lipid deposition and mitochondrial dysfunction are hallmarks of obesity and metabolic disorders.
- Saturated fatty acids (SFAs) promote these conditions, while unsaturated fatty acids (UFAs) offer protective effects.
- The precise signaling mechanisms by which SFAs and UFAs influence mitochondrial function remain unclear.
Purpose of the Study:
- To elucidate the differential signaling pathways of SFAs and UFAs in regulating mitochondrial quality.
- To investigate the role of lysophosphatidylinositol (LPI) in mediating the effects of saturated fatty acids on mitochondrial homeostasis.
- To identify key proteins and molecular events involved in the degradation of mitophagy receptors.
Main Methods:
- Investigated the impact of palmitic acid (PA) and oleic acid (OA) on LPI production and FUNDC1 stability in vitro.
- Utilized biochemical assays to analyze FUNDC1 dimerization, acetylation, and ubiquitination.
- Examined the effects of a fructose-, palmitate-, and cholesterol-enriched (FPC) diet on FUNDC1 in a non-alcoholic steatohepatitis (NASH) mouse model.
Main Results:
- Palmitic acid (PA), but not oleic acid (OA), significantly increased LPI production.
- Elevated LPI levels promoted the monomerization and degradation of the mitophagy receptor FUNDC1.
- PA-induced FUNDC1 degradation involved dissociation of HDAC3, interaction with Tip60, and ubiquitination by MARCH5.
- OA antagonized PA-induced LPI accumulation and FUNDC1 degradation.
- An FPC diet induced FUNDC1 degradation in a NASH mouse model.
Conclusions:
- SFAs, via increased LPI production, disrupt mitochondrial quality control by promoting FUNDC1 degradation.
- UFAs counteract the detrimental effects of SFAs on mitochondrial quality.
- This study uncovers a novel signaling axis linking lipid metabolism to mitochondrial quality regulation, with implications for metabolic disorders.
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