FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity
FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity
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FUNDC1 与 FBXL2 相互作用，通过 IP3R3 依赖性方式在肥胖症中控制线粒体完整性和心脏功能
DOI：
10.1126/sciadv.abc8561
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
Zhang, Yingmei
中科院分区：
文献类型：
--
作者：
Ren, Jun;Sun, Mingming;Zhang, Yingmei
线粒体自噬受体 FUNDC1 与 FBXL2 相互作用，可维持肥胖患者的线粒体 Ca2+ 稳态和心脏功能。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（包含 1 的 FUN14 结构域）和人 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，通过降解 IP3R3（肌醇 1,4,5-三磷酸受体 3 型）作为线粒体 Ca2+ 稳态的看门人。 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 升高和 Ca2+ 超载。质谱和免疫共沉淀分析揭示了 FUNDC1 和 FBXL2 之间的相互作用。 Fbox (Delta-F-box) 的截短突变体脱离了 FBXL2 与 FUNDC1 的相互作用。 FBXL2 的激活或转染、IP3R3 的抑制减轻，而 FBXL2 定位的破坏则使脂毒性诱导的心脏损伤敏感。 FUNDC1 缺陷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 之间的相互作用在保持肥胖心脏线粒体 Ca2+ 稳态和心脏功能方面发挥着重要作用。
The mitophagy receptor FUNDC1 interacts with FBXL2 to preserve mitochondrial Ca2+ homeostasis and cardiac function in obesity. 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.