FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32938669.
- Also identified by DOI 10.1126/sciadv.abc8561 and PMC identifier 7494344.
- Licence recorded as CC BY-NC.
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Abstract
Defective mitophagy is causally linked to obesity complications. Here, we identified an interaction between mitophagy protein FUNDC1 (FUN14 domain containing 1) and receptor subunit of human SCF (SKP1/cullin/F-box protein) ubiquitin ligase complex FBXL2 as a gatekeeper for mitochondrial Ca<sup>2+</sup> homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1<sup>-/-</sup> mice accentuated high-fat diet-induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca<sup>2+</sup> overload. Mass spectrometry and co-immunoprecipitation analyses revealed an interaction between FUNDC1 and FBXL2. Truncated mutants of Fbox (Delta-F-box) disengaged FBXL2 interaction with FUNDC1. Activation or transfection of FBXL2, inhibition of IP3R3 alleviated, whereas disruption of FBXL2 localization sensitized lipotoxicity-induced cardiac damage. FUNDC1 deficiency accelerated and decelerated palmitic acid-induced degradation of FBXL2 and IP3R3, respectively. Our data suggest an essential role for interaction between FUNDC1 and FBXL2 in preserving mitochondrial Ca<sup>2+</sup> homeostasis and cardiac function in obese hearts.