RRC ID 76502
Author Nagao T, Shintani Y, Hayashi T, Kioka H, Kato H, Nishida Y, Yamazaki S, Tsukamoto O, Yashirogi S, Yazawa I, Asano Y, Shinzawa-Itoh K, Imamura H, Suzuki T, Suzuki T, Goto YI, Takashima S.
Title Higd1a improves respiratory function in the models of mitochondrial disorder.
Journal FASEB J
Abstract 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.
Volume 34(1)
Pages 1859-1871
Published 2020-1-1
DOI 10.1096/fj.201800389R
PMID 31914602
MeSH Adenosine Triphosphate / metabolism Animals Animals, Genetically Modified Biological Transport / physiology Cell Line Cytochromes c / metabolism Electron Transport / physiology* Electron Transport Complex IV / metabolism HEK293 Cells Humans Hypoxia / metabolism Intracellular Signaling Peptides and Proteins / metabolism* Kinetics Mitochondria / metabolism* Mitochondrial Diseases / metabolism* Mitochondrial Proteins / metabolism* Oxidation-Reduction Respiration Zebrafish / metabolism
IF 4.966
Zebrafish hspGFF3A