14
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The mitophagy receptor FUNDC1 interacts with FBXL2 to preserve mitochondrial Ca 2+ homeostasis and cardiac function 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ homeostasis and cardiac function in obese hearts.

          Related collections

          Most cited references37

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy

          Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            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

            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 ( Fundc1 f/Y /Cre αMyHC+/− ), 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 (IP 3 R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP 3 R2 and Ca 2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP 3 R2 and Ca 2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca 2+ levels in ER whereas Fundc1 overexpression lowered ER Ca 2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca 2+ 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. Fundc1 f/Y /Cre αMyHC+/− mice but not their littermate control mice ( Fundc1 wt/Y /Cre αMyHC+/− ) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1 f/Y /Cre αMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1 f/Y /Cre αMyHC+/− 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 IP 3 R2 to modulate ER Ca 2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP 3 R2 interaction lowers the levels of Ca 2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Targeting autophagy in obesity: from pathophysiology to management

                Bookmark

                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                September 2020
                16 September 2020
                : 6
                : 38
                : eabc8561
                Affiliations
                [1 ]Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
                [2 ]Department of Pathology, University of Washington Seattle, Seattle, WA 98195, USA.
                [3 ]University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
                [4 ]Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.
                [5 ]Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5185715179, Iran.
                [6 ]Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
                [7 ]Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510000, China.
                [8 ]Diabetes and Cardiovascular Research Center, University of Missouri Columbia, Columbia, MO 65212, USA.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: zhangym197951@ 123456126.com
                Author information
                http://orcid.org/0000-0002-0275-0783
                http://orcid.org/0000-0002-3117-7066
                http://orcid.org/0000-0001-8138-7275
                http://orcid.org/0000-0002-3667-2605
                http://orcid.org/0000-0001-5685-066X
                http://orcid.org/0000-0001-7686-1534
                Article
                abc8561
                10.1126/sciadv.abc8561
                7494344
                32938669
                f18acf07-9026-427f-b53b-9c4f70778200
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 18 May 2020
                : 03 August 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 91749128
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81770261
                Funded by: doi http://dx.doi.org/10.13039/501100005150, Chinese Academy of Medical Sciences;
                Award ID: 2019-RC-HL-021
                Funded by: doi http://dx.doi.org/10.13039/501100013290, National Key Research and Development Program of China Stem Cell and Translational Research;
                Award ID: 2017YFA0506000
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Cell Biology
                Physiology
                Physiology
                Custom metadata
                Lou Notario

                Comments

                Comment on this article