Abstract
Mitochondrial respiratory supercomplex formation requires HIG2A protein, which also has been associated with cell proliferation and cell survival under hypoxia. HIG2A protein localizes in mitochondria and nucleus. DNA methylation and mRNA expression of the HIGD2A gene show significant alterations in several cancers, suggesting a role for HIG2A in cancer biology. The present work aims to understand the dynamics of the HIG2A subcellular localization under cellular stress. We found that HIG2A protein levels increase under oxidative stress. H2O2 shifts HIG2A localization to the mitochondria, while rotenone shifts it to the nucleus. HIG2A protein colocalized at a higher level in the nucleus concerning the mitochondrial network under normoxia and hypoxia (2% O2). Hypoxia (2% O2) significantly increases HIG2A nuclear colocalization in C2C12 cells. In HEK293 cells, chemical hypoxia with CoCl2 (>1% O2) and FCCP mitochondrial uncoupling, the HIG2A protein decreased its nuclear localization and shifted to the mitochondria. This suggests that the HIG2A distribution pattern between the mitochondria and the nucleus depends on stress and cell type. HIG2A protein expression levels increase under cellular stresses such as hypoxia and oxidative stress. Its dynamic distribution between mitochondria and the nucleus in response to stress factors suggests a new communication system between the mitochondria and the nucleus.
Highlights
Respiratory supercomplexes represent a regulatory unit of cellular respiration, stabilizing respiratory OXPHOS complexes, enhancing substrate channeling, and minimizing the generation of reactive oxygen species (ROS) during electron transfer reactions [1,2,3,4,5,6,7]
HEK293 cells that were knocked-out for the HIGD2A gene showed a decrease in mitochondrial respiration, a reduction in the activity of complex III, a decrease in the interaction of complex IV with complex III, a reduction of the biogenesis of complex IV, and a decline in the total levels of complex I [11]
HIG2A protein levels are increased by cellular stress such as hypoxia and oxidative stress
Summary
Respiratory supercomplexes represent a regulatory unit of cellular respiration, stabilizing respiratory OXPHOS complexes, enhancing substrate channeling, and minimizing the generation of reactive oxygen species (ROS) during electron transfer reactions [1,2,3,4,5,6,7]. Proteins that mediate and regulate the stability and assembly of respiratory supercomplexes have been described, e.g., the SURF1 protein, the MCJ/DnaJC15 co-chaperone, the COX7RP protein, the RCF1 protein, and the HIG2A protein. The RCF1 protein enables the association between complex III and complex IV, promoting the assembly of OXPHOS supercomplexes [8,9,10]. The knockdown of HIGD2A in human HeLa cells and mouse C2C12 cells altered the formation of I1 + III2 + IV1–4 supercomplex through the complex IV release [8]. Timón-Gomez et al (2020) confirmed that HIG2A is required to assemble the COX3 subunit of human complex IV and coordinate supercomplex formation by participating in the association between complex III and IV [11]. HEK293 cells that were knocked-out for the HIGD2A gene showed a decrease in mitochondrial respiration, a reduction in the activity of complex III, a decrease in the interaction of complex IV with complex III, a reduction of the biogenesis of complex IV, and a decline in the total levels of complex I [11]
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