LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane

Shan Zhang; Yabo Guo; Gio Fidelito; David R L Robinson; Chao Liang; Radiance Lim; Zoë Bichler; Ruiyang Guo; Gaoqi Wu; He Xu; Quan D Zhou; Brijesh K Singh; Paul Yen; Dennis Kappei; David A Stroud; Lena Ho

doi:10.1016/j.isci.2023.107558

LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane

iScience. 2023 Aug 7;26(9):107558. doi: 10.1016/j.isci.2023.107558. eCollection 2023 Sep 15.

Authors

Shan Zhang^{1

2}, Yabo Guo¹, Gio Fidelito², David R L Robinson³, Chao Liang², Radiance Lim², Zoë Bichler⁴, Ruiyang Guo¹, Gaoqi Wu⁵, He Xu⁵, Quan D Zhou⁵, Brijesh K Singh², Paul Yen², Dennis Kappei^{6

7

8}, David A Stroud^{3

9

10}, Lena Ho²

Affiliations

¹ Department of Biochemistry, Department of Cardiology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
² Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
³ Department of Biochemistry and Pharmacology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, VIC 3010, Australia.
⁴ Behavioral Neuroscience Laboratory, National Neuroscience Institute, Singapore 308433, Singapore.
⁵ Institute of Immunology, Department of Surgical Oncology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
⁷ Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
⁸ NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
⁹ Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3010, Australia.
¹⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3010, Australia.

Abstract

LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

Keywords: Biochemistry; Biological sciences; Cell biology; Molecular biology.