Working Paper Article Version 1 This version is not peer-reviewed

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1Deficiency

Version 1 : Received: 9 February 2021 / Approved: 10 February 2021 / Online: 10 February 2021 (10:58:33 CET)

A peer-reviewed article of this Preprint also exists.

Douiev, L.; Miller, C.; Ruppo, S.; Benyamini, H.; Abu-Libdeh, B.; Saada, A. Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency. Cells 2021, 10, 452. Douiev, L.; Miller, C.; Ruppo, S.; Benyamini, H.; Abu-Libdeh, B.; Saada, A. Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency. Cells 2021, 10, 452.

Journal reference: Cells 2021, 10, 452
DOI: 10.3390/cells10020452

Abstract

Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF), and compared to patient's cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were carried out by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrate elevated COX4-2 levels in the COX4-1-deficient cells with a concomitant HIF-1α stabilization, nuclear localization and upregulated hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α has the are upregulated, also in normoxia as a compensatory mechanism in COX4-1 deficiency.

Keywords

Mitochondria; cytochrome c oxidase; COX4-1; COX4-2; HIF-1α

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