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

Overview

Journal Circulation

Specialty Cardiology & Vascular Diseases

Date 2017 Sep 25

PMID 28942427

Citations 141

Authors

Shengnan Wu

Qiulun Lu

Qilong Wang

Ye Ding

Zejun Ma

Xiaoxiang Mao

Kai Huang

Zhonglin Xie

Ming-Hui Zou

Affiliations

Soon will be listed here.

Abstract

Background: FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine whether FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and intact hearts.

Methods: The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific gene knockout ( ), 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 (IPR2). ablation disrupted MAMs and reduced the levels of IPR2 and Ca in both mitochondria and cytosol, whereas overexpression of increased the levels of IPR2 and Ca in both mitochondria and cytosol. Consistently, ablation increased Ca levels in ER, whereas overexpression lowered ER Ca levels. Further, ablation in cardiomyocytes elongated mitochondria and compromised mitochondrial functions. Mechanistically, we found that ablation-induced reduction of intracellular Ca levels suppressed mitochondrial fission 1 protein () expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the promoter. mice but not their littermate control mice ( ) exhibited cardiac dysfunction. The ligation of the left ventricle artery of mice caused more severe cardiac dysfunction than those in sham-treated mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in patients with heart failure.

Conclusions: We conclude that FUNDC1 binds to IPR2 to modulate ER Ca release into mitochondria and cytosol. Further, a disruption of the FUNDC1 and IPR2 interaction lowers the levels of Ca in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.

Citing Articles

Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology.

Kichuk T, Avalos J Int J Mol Sci. 2025; 26(5).

PMID: 40076772 PMC: 11899761. DOI: 10.3390/ijms26052152.

Mitochondria-associated endoplasmic reticulum membranes and myocardial ischemia: from molecular mechanisms to therapeutic strategies.

Chen C, Dai G, Fan M, Wang X, Niu K, Gao W J Transl Med. 2025; 23(1):277.

PMID: 40050915 PMC: 11884070. DOI: 10.1186/s12967-025-06262-3.

Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.

Latchman N, Stevens T, Bedi K, Prosser B, Margulies K, Elrod J bioRxiv. 2025; .

PMID: 39975328 PMC: 11838275. DOI: 10.1101/2025.01.29.635600.

Visual Analysis of Research Hotspots and Trends on Mitochondria-Associated Membranes in the Past 20 Years-Focused on Neurodegenerative Diseases.

Du Y, Duan C, Zhu X, Lyu M, Chen J, Wei Y Mol Neurobiol. 2025; .

PMID: 39964584 DOI: 10.1007/s12035-025-04722-x.

The roles of mitochondria in global and local intracellular calcium signalling.

Cartes-Saavedra B, Ghosh A, Hajnoczky G Nat Rev Mol Cell Biol. 2025; .

PMID: 39870977 DOI: 10.1038/s41580-024-00820-1.

References

Giorgi C, Missiroli S, Patergnani S, Duszynski J, Wieckowski M, Pinton P . Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid Redox Signal. 2015; 22(12):995-1019. DOI: 10.1089/ars.2014.6223. View

Mao K, Wang K, Liu X, Klionsky D . The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev Cell. 2013; 26(1):9-18. PMC: 3720741. DOI: 10.1016/j.devcel.2013.05.024. View

Marriott K, Prasad M, Thapliyal V, Bose H . σ-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation. J Pharmacol Exp Ther. 2012; 343(3):578-86. PMC: 3500540. DOI: 10.1124/jpet.112.198168. View

Rowland A, Voeltz G . Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 2012; 13(10):607-25. PMC: 5111635. DOI: 10.1038/nrm3440. View

Lee J, Westrate L, Wu H, Page C, Voeltz G . Multiple dynamin family members collaborate to drive mitochondrial division. Nature. 2016; 540(7631):139-143. PMC: 5656044. DOI: 10.1038/nature20555. View

Stojanovski D, Koutsopoulos O, Okamoto K, Ryan M . Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci. 2004; 117(Pt 7):1201-10. DOI: 10.1242/jcs.01058. View

Fentzke R, Korcarz C, Lang R, Lin H, Leiden J . Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest. 1998; 101(11):2415-26. PMC: 508831. DOI: 10.1172/JCI2950. View

Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P . Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012; 14(2):177-85. DOI: 10.1038/ncb2422. View

Lee Y, Jeong S, Karbowski M, Smith C, Youle R . Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004; 15(11):5001-11. PMC: 524759. DOI: 10.1091/mbc.e04-04-0294. View

10.

Fonseca A, Moreira P, Oliveira C, Cardoso S, Pinton P, Pereira C . Amyloid-beta disrupts calcium and redox homeostasis in brain endothelial cells. Mol Neurobiol. 2014; 51(2):610-22. DOI: 10.1007/s12035-014-8740-7. View

11.

Muller F, Boknik P, Knapp J, Luss H, Neumann J, Vahlensieck U . Quantification of the cAMP response element binding protein in ventricular nuclear protein from failing and nonfailing human hearts. Biochem Biophys Res Commun. 1997; 236(2):351-4. DOI: 10.1006/bbrc.1997.6971. View

12.

Ni H, Williams J, Ding W . Mitochondrial dynamics and mitochondrial quality control. Redox Biol. 2014; 4:6-13. PMC: 4309858. DOI: 10.1016/j.redox.2014.11.006. View

13.

Sebastian D, Hernandez-Alvarez M, Segales J, Sorianello E, Munoz J, Sala D . Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A. 2012; 109(14):5523-8. PMC: 3325712. DOI: 10.1073/pnas.1108220109. View

14.

Neubauer S . The failing heart--an engine out of fuel. N Engl J Med. 2007; 356(11):1140-51. DOI: 10.1056/NEJMra063052. View

15.

Muller F, Neumann J, Schmitz W . Transcriptional regulation by cAMP in the heart. Mol Cell Biochem. 2000; 212(1-2):11-7. View

16.

Friedman J, Voeltz G . The ER in 3D: a multifunctional dynamic membrane network. Trends Cell Biol. 2011; 21(12):709-17. PMC: 3221873. DOI: 10.1016/j.tcb.2011.07.004. View

17.

Zhang Q, Wu J, Wu R, Ma J, Du G, Jiao R . DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection. Biochem J. 2012; 447(2):261-9. DOI: 10.1042/BJ20120598. View

18.

Kuznetsov A, Hermann M, Saks V, Hengster P, Margreiter R . The cell-type specificity of mitochondrial dynamics. Int J Biochem Cell Biol. 2009; 41(10):1928-39. DOI: 10.1016/j.biocel.2009.03.007. View

19.

Han X, Lu Y, Li S, Kaitsuka T, Sato Y, Tomizawa K . CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008; 182(3):573-85. PMC: 2500141. DOI: 10.1083/jcb.200802164. View

20.

Lackner L . Shaping the dynamic mitochondrial network. BMC Biol. 2014; 12:35. PMC: 4035697. DOI: 10.1186/1741-7007-12-35. View