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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ homeostasis and cardiac function in obese hearts.

有缺陷的线粒体自噬与肥胖并发症有因果关系。在这里，我们确定了线粒体自噬蛋白 FUNDC1（含有 1 的 FUN14 结构域）和人类 SCF 受体亚基（SKP1/cullin/F-box 蛋白）泛素连接酶复合物 FBXL2 之间的相互作用，它通过降解IP3R3 作为线粒体 Ca ²⁺稳态的看门人。肌醇 1,4,5-三磷酸受体 3)。FUNDC1 ^-/-小鼠中 FUNDC1 的缺失加剧了高脂饮食诱导的心脏重塑、功能和线粒体异常、细胞死亡、IP3R3 和 Ca ^2+升高超载。质谱和共免疫沉淀分析揭示了 FUNDC1 和 FBXL2 之间的相互作用。Fbox (Delta-F-box) 的截断突变体使 FBXL2 与 FUNDC1 相互作用。FBXL2 的激活或转染，IP3R3 的抑制减轻，而 FBXL2 定位的破坏使脂毒性诱导的心脏损伤敏感。FUNDC1 缺乏分别加速和减缓棕榈酸诱导的 FBXL2 和 IP3R3 降解。我们的数据表明 FUNDC1 和 FBXL2 之间的相互作用在维持肥胖心脏的线粒体 Ca ²⁺稳态和心脏功能方面具有重要作用。