PMID- 31914602 OWN - NLM STAT- MEDLINE DCOM- 20200706 LR - 20201214 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 34 IP - 1 DP - 2020 Jan TI - Higd1a improves respiratory function in the models of mitochondrial disorder. PG - 1859-1871 LID - 10.1096/fj.201800389R [doi] AB - The respiratory chain (RC) transports electrons to form a proton motive force that is required for ATP synthesis in the mitochondria. RC disorders cause mitochondrial diseases that have few effective treatments; therefore, novel therapeutic strategies are critically needed. We previously identified Higd1a as a positive regulator of cytochrome c oxidase (CcO) in the RC. Here, we test that Higd1a has a beneficial effect by increasing CcO activity in the models of mitochondrial dysfunction. We first demonstrated the tissue-protective effects of Higd1a via in situ measurement of mitochondrial ATP concentrations ([ATP](mito)) in a zebrafish hypoxia model. Heart-specific Higd1a overexpression mitigated the decline in [ATP](mito) under hypoxia and preserved cardiac function in zebrafish. Based on the in vivo results, we examined the effects of exogenous HIGD1A on three cellular models of mitochondrial disease; notably, HIGD1A improved respiratory function that was coupled with increased ATP synthesis and demonstrated cellular protection in all three models. Finally, enzyme kinetic analysis revealed that Higd1a significantly increased the maximal velocity of the reaction between CcO and cytochrome c without changing the affinity between them, indicating that Higd1a is a positive modulator of CcO. These results corroborate that Higd1a, or its mimic, provides therapeutic options for the treatment of mitochondrial diseases. CI - (c) 2019 Federation of American Societies for Experimental Biology. FAU - Nagao, Takemasa AU - Nagao T AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Shintani, Yasunori AU - Shintani Y AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Hayashi, Takaharu AU - Hayashi T AD - Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan. FAU - Kioka, Hidetaka AU - Kioka H AD - Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan. FAU - Kato, Hisakazu AU - Kato H AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Nishida, Yuya AU - Nishida Y AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. AD - Japan Science and Technology Agency-Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan. FAU - Yamazaki, Satoru AU - Yamazaki S AD - Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan. FAU - Tsukamoto, Osamu AU - Tsukamoto O AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Yashirogi, Shohei AU - Yashirogi S AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Yazawa, Issei AU - Yazawa I AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. FAU - Asano, Yoshihiro AU - Asano Y AD - Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan. FAU - Shinzawa-Itoh, Kyoko AU - Shinzawa-Itoh K AD - Department of Life Science, University of Hyogo, Kobe, Japan. FAU - Imamura, Hiromi AU - Imamura H AD - Graduate School of Biostudies, Kyoto University, Kyoto, Japan. FAU - Suzuki, Takeo AU - Suzuki T AD - Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo, Japan. FAU - Suzuki, Tsutomu AU - Suzuki T AD - Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo, Japan. FAU - Goto, Yu-Ichi AU - Goto YI AD - Department of Child Neurology, National Center Hospital of Neurology and Psychiatry (NCNP), Kodaira, Japan. FAU - Takashima, Seiji AU - Takashima S AD - Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan. AD - Japan Science and Technology Agency-Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191210 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (HIGD1A protein, human) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Mitochondrial Proteins) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - 9007-43-6 (Cytochromes c) RN - EC 1.9.3.1 (Electron Transport Complex IV) SB - IM MH - Adenosine Triphosphate/metabolism MH - Animals MH - Animals, Genetically Modified MH - Biological Transport/physiology MH - Cell Line MH - Cytochromes c/metabolism MH - Electron Transport/*physiology MH - Electron Transport Complex IV/metabolism MH - HEK293 Cells MH - Humans MH - Hypoxia/metabolism MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Kinetics MH - Mitochondria/*metabolism MH - Mitochondrial Diseases/*metabolism MH - Mitochondrial Proteins/*metabolism MH - Oxidation-Reduction MH - Respiration MH - Zebrafish/metabolism OTO - NOTNLM OT - cytochrome c oxidase OT - hypoxia OT - mitochondria OT - respiratory chain EDAT- 2020/01/10 06:00 MHDA- 2020/07/07 06:00 CRDT- 2020/01/10 06:00 PHST- 2018/02/27 00:00 [received] PHST- 2018/05/26 00:00 [revised] PHST- 2018/06/12 00:00 [accepted] PHST- 2020/01/10 06:00 [entrez] PHST- 2020/01/10 06:00 [pubmed] PHST- 2020/07/07 06:00 [medline] AID - 10.1096/fj.201800389R [doi] PST - ppublish SO - FASEB J. 2020 Jan;34(1):1859-1871. doi: 10.1096/fj.201800389R. Epub 2019 Dec 10.