FUNDC1 interacts with FBXL2 to govern mitochondrial integrity and cardiac function through an IP3R3-dependent manner in obesity

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 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.

The Protective Effect of 1,25(OH)2D3 on Myocardial Function is Mediated via Sirtuin 3-Regulated Fatty Acid Metabolism

“…A high-fat diet intake can cause undesirable changes in cardiac structure and function. Mice on a high-fat diet will develop obesity, cardiac remodeling, contractile dysfunction, mitochondrial abnormalities, an abnormal ultrastructure, inflammation, cardiomyocyte apoptosis, etc ( Ren et al, 2020 ; Gong et al, 2020 ; Zhang and Ren, 2016 ). Our experimental results were in agreement with some of the above ( Figures 2D , 3D,E , 4D ).…”

LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity

“…This coincides with the finding that excessive mitophagy leads to insufficient energy production and apoptosis in vascular smooth muscle cells within advanced atherosclerotic plaques 18 . However, mitophagy cannot be completely abolished, and moderate mitophagy is important for cardiac structure and function 16 , 32 . In the present study, we also found that reduced mitochondrial membrane potential upon PA treatment implies a need for mitophagy to some extent for clearing damaged mitochondria.…”

“…With regard to the pathways triggering mitophagy, the Parkin pathway has been reported to be downregulated in hearts of both genetic obesity and high-fat-fed mice 16 , 32 . In contrast, other studies have shown an increasing trend of Parkin-dependent mitophagy in high-fat diet-fed mice 33 , 34 .…”

Structure and Function of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases

“…FUNDC1-mediated mitophagy is confirmed as directly related to MAMs via binding to IP3R2 to mediate IP3R-dependent Ca 2+ signaling from ER to mitochondria and cytoplasm [125]. When FUNDC1 expression level is decreased, the intracellular Ca 2+ decreases, and Fis1 expression level is inhibited through Ca 2+ -sensitive CREB, leading to mitochondrial dysfunction [126].…”