Tissue‐ and Condition‐Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease

Abstract

Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain and catalyzes the transfer of electrons from cytochrome c to oxygen. COX consists of 14 subunits, three and eleven encoded, respectively, by the mitochondrial and nuclear DNA. Tissue- and condition-specific isoforms have only been reported for COX but not for the other oxidative phosphorylation complexes, suggesting a fundamental requirement to fine-tune and regulate the essentially irreversible reaction catalyzed by COX. This article briefly discusses the assembly of COX in mammals and then reviews the functions of the six nuclear-encoded COX subunits that are expressed as isoforms in specialized tissues including those of the liver, heart and skeletal muscle, lung, and testes: COX IV-1, COX IV-2, NDUFA4, NDUFA4L2, COX VIaL, COX VIaH, COX VIb-1, COX VIb-2, COX VIIaH, COX VIIaL, COX VIIaR, COX VIIIH/L, and COX VIII-3. We propose a model in which the isoforms mediate the interconnected regulation of COX by (1) adjusting basal enzyme activity to mitochondrial capacity of a given tissue; (2) allosteric regulation to adjust energy production to need; (3) altering proton pumping efficiency under certain conditions, contributing to thermogenesis; (4) providing a platform for tissue-specific signaling; (5) stabilizing the COX dimer; and (6) modulating supercomplex formation.

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

“…Similar to in vivo Tyr48 phosphorylation, the phosphomimetic Tyr48Glu mutant showed a reduced maximum turnover rate compared to the wild type (WT), suggesting that it is a useful model (66). The reduction of maximum turnover in the reaction with COX was less pronounced with heart COX than with liver COX, most likely because of the presence of 3 heart-specific COX subunit isoforms (VIa-H, VIIa-H, and VIII-H) (67). Furthermore, a higher K m was observed, suggesting a lower binding affinity toward heart COX (66).…”

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

“…COX IV subunit 1 contains heme a and a3 (not found in complexes I-III and V) Heme a is made in a series of sub-synthesis hemylation steps carried out by heme a synthase and is essential for proper folding and stability of COX IV (Kim et al, 2012) (Figure 7). COX IV is particularly sensitive to FECH inhibition-induced heme depletion, possibly affecting the hemylation process downstream of protoheme synthesis, leading to a smaller pool of heme a (Atamna et al, 2001;Sinkler et al, 2017). COX10 and COX15, proteins responsible for conversion of heme b (synthesized by FECH) to heme a were among the top-scoring genes that caused ETC disruption after heme depletion in acute myeloid leukemia cells (Lin et al, 2019), further suggesting the significance of heme a supply as a mediator of mitochondrial function, since it is a prosthetic group specifically in COX IV holoenzyme.…”

Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1

“…The catalytic core of COX is composed of three subunits (COX I-III), encoded by the mitochondrial genome (MT-CO1-3), and their prosthetic groups. COX I, II and III are surrounded by 11 nuclear-encoded subunits, many of which are expressed as tissue-specific isoforms, that are suggested to perform an insulating or regulatory role 1 . Assembly of the COX holoenzyme is a complex module-based process that occurs around COX I-III 2 .…”