Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo

Abstract

Background FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in intact hearts. Methods The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure. Results In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in the patients with heart failure. Conclusions We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.

Metabolic implications of organelle–mitochondria communication

“…In addition to its role in mitochondrial dynamics, FUNDC1 interacts with the ER Ca 2+ channel IP3R2 and promotes Ca 2+ flux to mitochondria [76]. The depletion of Fundc1 in mouse cardiomyocytes and H9c2 myoblasts leads to a decrease in IP3R2 and colocalization between mitochondria and the ER [76]. The authors of this study proposed that FUNDC1 and IP3R2 act together as a tethering complex of mitochondria and the ER.…”

“…Moreover, the chemical inhibition of DRP1 in PC12 rat pheochromocytoma cells leads to a reduction in ER Ca 2+ release compared to untreated cells and concomitantly decreases mitochondrial Ca 2+ intake [75]. Fundc1 overexpression in mouse cardiomyocytes increases Ca 2+ release from the ER to mitochondria [76]. The role of FUNDC1 in Ca 2+ release will be further assessed in this review.…”

“…The authors of this study proposed that FUNDC1 and IP3R2 act together as a tethering complex of mitochondria and the ER. FUNDC1 ablation also decreases the levels of the MAM maintenance protein PACS2 [76]. Inhibition of ER Ca 2+ uptake by SERCA initiates UPR and eventually provokes apoptosis [95].…”

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…Under hypoxia condition, the FUNDC1 mRNA and protein levels are dramatically downregulated, which may be attributable to mitophagy. No conserved HIF‐1 recognition site is found in the promoter region of FUNDC1 . FUNDC1 can effectively activate the autophagy mechanism and promote mitophagy.…”

“…No conserved HIF-1 recognition site is found in the promoter region of FUNDC1. 43 FUNDC1 can effectively activate the autophagy mechanism and promote mitophagy. The FUNDC1-dependent mitophagy may also contain a Beclin1-independent component.…”