Higd1a improves respiratory function in the models of mitochondrial disorder

Abstract

oxidoreductase iron-sulfur protein 4; NSUN3, NOL1/NOP2/Sun domain-containing protein 3; OCR, oxygen consumption rate; OG, n-octyl-β-D-glucoside; OXPHOS, oxidative phosphorylation; RC, respiratory chain; ROS, reactive oxygen species. Correspondence AbstractThe 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. Heartspecific 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 1860 | NAGAO et Al.

In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance

“…This in vivo imaging system should be useful for the investigation of diseases related to energy metabolism such as ischemic heart diseases, cardiomyopathies, and metabolic diseases. 33 Taken together, our results show that G0s2 works to maintain mitochondrial ATP production and tissue function, even under hypoxic conditions. Enhancing the expression level and/or function of G0s2 could be beneficial for the treatment of hypoxia-related disorders such as ischemic heart disease.…”

“…In other words, using Mit‐ATeam zebrafish, we can simultaneously assess mitochondrial ATP production and cardiac function. This in vivo imaging system should be useful for the investigation of diseases related to energy metabolism such as ischemic heart diseases, cardiomyopathies, and metabolic diseases …”

Multi-omics analyses of human colorectal cancer revealed three mitochondrial genes potentially associated with poor outcomes of patients

“…As we have known, the three selected-out genes all locate in mitochondria. HIGD1A is identified as a regulator of cytochrome c oxidase and modulates respiratory functions [ 20 , 21 ]. SUCLG2 is a subunit of succinyl-CoA synthetase, involving the tricarboxylic acid cycle (TCA) [ 22 , 23 ].…”

“…The function of HIGD1A is a positive regulator of cytochrome C oxidase and can induce apoptosis under hypoxia. It is associated with hypoxia microenvironment of cells, and when hypoxia-induced factors 1 (HIF-1) lacks, expression of HIGD1A will increases, cooperated with electron transport proteins reducing oxygen consumption and ROS production [ 20 , 21 ]. SLC25A24 is a carrier protein that exchanges ATP-Mg for phosphate [ 24 , 25 ].…”

HIGD-Driven Regulation of Cytochrome c Oxidase Biogenesis and Function

“…For example, hypoxia regimens effectively improved survival and attenuated symptoms in animal models of mitochondrial diseases [85,86]. Similarly, the expression of HIGD1A in different cellular and animal models of mitochondrial disease was shown to attenuate their deleterious phenotypes by increasing CIV activity and ATP production while decreasing ROS levels [32]. Consequently, elucidating the mechanism of action of HIGD proteins under low oxygen levels could reveal new potential therapeutic candidates, mimicking or enhancing the HIGD1A mechanism of action.…”