| First Author | Ren J | Year | 2020 |
| Journal | Sci Adv | Volume | 6 |
| Issue | 38 | PubMed ID | 32938669 |
| Mgi Jnum | J:314155 | Mgi Id | MGI:6797035 |
| Doi | 10.1126/sciadv.abc8561 | Citation | Ren J, et al. (2020) FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity. Sci Adv 6(38) |
| abstractText | 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(2+) homeostasis through degradation of IP3R3 (inositol 1,4,5-trisphosphate receptor type 3). Loss of FUNDC1 in FUNDC1(-/-) mice accentuated high-fat diet-induced cardiac remodeling, functional and mitochondrial anomalies, cell death, rise in IP3R3, and Ca(2+) 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(2+) homeostasis and cardiac function in obese hearts. |
