MOCCI: A mito-SEP that modulates inflammation outcome through regulating electron transport chain Complex IV Cheryl Q.E. Lee1, Baptiste Kerouanton2, Sonia Chothani2, Shan Zhang2, Ying Chen3, Chinmay Kumar Mantri4, Daniella Helena Hock5, Radiance Lim2, Rhea Nadkarni2, Vinh Thang Huynh3,6, Daryl Lim7, Wei Leong Chew7, Franklin L. Zhong8,9, David Arthur Stroud5, Sebastian Schafer2,10, Vinay Tergaonkar3,11, Ashley L. St John4,12,13, Owen J.L. Rackham2, Lena Ho1,2,3,* 1Institute of Medical Biology, A*STAR, 8a Biomedical Grove, Singapore 138648 2Duke-NUS Medical School, Program in Cardiovascular and Metabolic Disorders, 8 College Road, Singapore 169857 3Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Dr, Singapore 138673 4Duke-NUS Medical School, Program in Emerging Infectious Diseases, 8 College Road, Singapore 169857 5Department of Biochemistry and Molecular Biology, The Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, 30 Flemington Rd, Parkville VIC 3052, Melbourne, Australia 6Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232 7Genome Institute Singapore, A*STAR, 60 Biopolis St, Singapore 138672 8Nanyang Technological University, Skin Diseases and Wound Repair Program, 11 Mandalay Road, Singapore 308232 9Skin Research Institute of Singapore, A*STAR, 11 Mandalay Road, Singapore 308232 10National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Dr, Singapore 169609 11Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597 12Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597 13Department of Pathology, Duke University Medical Center, 10 Duke Medicine Cir, NC 27710-1000, Durham, North Carolina, USA Inflammation is a tightly controlled process that must be resolved in a timely manner. Mitochondrial metabolism is crucial in regulating this process. Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria. Using ribosome profiling and RNA-sequencing of human aortic endothelial cells (HAECs), we identified novel mito-SEPs upregulated during inflammation, termed i-mito-SEPs. We report the discovery and deorphanization of Modulator of Cytochrome C oxidase during Inflammation (MOCCI), a 83 aa mitochondrial SEP (mito-SEP) that is specific to the inflamed state. MOCCI is a paralog of NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 4 (NDUFA4), the 14th subunit of the mitochondrial respiratory chain Complex IV (CIV). During inflammation, MOCCI replaces NDUFA4 in CIV, which leads to repressed CIV activity, lower membrane potential and reduced ROS production. These result in cyto-protective and anti-inflammatory effects. We propose that one of the mechanisms mito-SEPs control inflammation is via altering mitochondrial electron transport chain activity.
Institute of Cell and Molecular Biology, A*STAR, Singapore
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