Cytochrome c oxidase (COX), the terminal enzyme of mitochondrial electron transport chain, couples electron transport to oxygen with generation of proton gradient indispensable for the production of vast majority of ATP molecules in mammalian cells. The review summarizes current knowledge of COX structure and function of nuclear-encoded COX subunits, which may modulate enzyme activity according to various conditions. Moreover, some nuclear-encoded subunits posess tissue-specific and development-specific isoforms, possibly enabling fine-tuning of COX function in individual tissues. The importance of nuclear-encoded subunits is emphasized by recently discovered pathogenic mutations in patients with severe mitopathies. In addition, proteins substoichiometrically associated with COX were found to contribute to COX activity regulation and stabilization of the respiratory supercomplexes. Based on the summarized data, a model of three levels of quaternary COX structure is postulated. Individual structural levels correspond to subunits of the i) catalytic center, ii) nuclear-encoded stoichiometric subunits and iii) associated proteins, which may constitute several forms of COX with varying composition and differentially regulated function.

Department of Bioenergetics Institute of Physiology CAS Prague Czech Republic

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ABDULHAG UN, SOIFERMAN D, SCHUELER-FURMAN O, MILLER C, SHAAG A, ELPELEG O, EDVARDSON S, SAADA A. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. Eur J Hum Genet. 2015;23:159–164. doi: 10.1038/ejhg.2014.85. PubMed DOI PMC

ABU-LIBDEH B, DOUIEV L, AMRO S, SHAHROUR M, TA-SHMA A, MILLER C, ELPELEG O, SAADA A. Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. Eur J Hum Genet. 2017;25:1142–1146. doi: 10.1038/ejhg.2017.112. PubMed DOI PMC

ACÍN-PÉREZ R, FERNÁNDEZ-SILVA P, PELEATO ML, PÉREZ-MARTOS A, ENRÍQUEZ JA. Respiratory active mitochondrial supercomplexes. Mol Cell. 2008;32:529–539. doi: 10.1016/j.molcel.2008.10.021. PubMed DOI

ACÍN-PÉREZ R, GATTI DL, BAI Y, MANFREDI G. Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. Cell Metab. 2011;13:712–719. doi: 10.1016/j.cmet.2011.03.024. PubMed DOI PMC

ANDERSSON SGE, ZOMORODIPOUR A, ANDERSSON JO, SICHERITZ-PONTÉN T, ALSMARK UC, PODOWSKI RM, NASLUND AK, ERIKSSON A-SS, WINKLER HH, KURLAND CG, SICHERITZ-PONTÉN T, ALSMARK UC, PODOWSKI RM, NÄSLUND AK, ERIKSSON A-SS, WINKLER HH, KURLAND CG. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature. 1998;396:133–140. doi: 10.1038/24094. PubMed DOI

ANTHONY G, REIMANN A, KADENBACH B. Tissue-specific regulation of bovine heart cytochrome-c oxidase activity by ADP via interaction with subunit VIa. P Natl Acad Sci USA. 1993;90:1652–1656. doi: 10.1073/pnas.90.5.1652. PubMed DOI PMC

ARAS S, ARRABI H, PURANDARE N, HÜTTEMANN M, KAMHOLZ J, ZÜCHNER S, GROSSMAN LI. Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. BBA-Mol Cell Res. 2017;1864:440–448. doi: 10.1016/j.bbamcr.2016.11.029. PubMed DOI

ARAS S, BAI M, LEE I, SPRINGETT R, HÜTTEMANN M, GROSSMAN LI. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51. doi: 10.1016/j.mito.2014.10.003. PubMed DOI

ARAS S, PAK O, SOMMER N, FINLEY R, HÜTTEMANN M, WEISSMANN N, GROSSMAN LI. Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2. Nucleic Acids Res. 2013;41:2255–2266. doi: 10.1093/nar/gks1454. PubMed DOI PMC

ARNOLD S, KADENBACH B. Cell respiration is controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase. Eur J Biochem. 1997;249:350–354. doi: 10.1111/j.1432-1033.1997.t01-1-00350.x. PubMed DOI

BABCOCK GT, WIKSTRÖM M. Oxygen activation and the conservation of energy in cell respiration. Nature. 1992;356:301–309. doi: 10.1038/356301a0. PubMed DOI

BAERTLING F, AL-MURSHEDI F, SÁNCHEZ-CABALLERO L, AL-SENAIDI K, JOSHI NP, VENSELAAR H, Van den BRAND MAM, NIJTMANS LGJ, RODENBURG RJT. Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. Hum Mutat. 2017;38:692–703. doi: 10.1002/humu.23210. PubMed DOI

BALSA E, MARCO R, PERALES-CLEMENTE E, SZKLARCZYK R, CALVO E, LANDÁZURI MO, ENRÍQUEZ JA. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 2012;16:378–386. doi: 10.1016/j.cmet.2012.07.015. PubMed DOI

BENDER E, KADENBACH B. The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett. 2000;466:130–134. doi: 10.1016/S0014-5793(99)01773-1. PubMed DOI

BOCZONADI V, GIUNTA M, LANE M, TULINIUS M, SCHARA U, HORVATH R. Investigating the role of the physiological isoform switch of cytochrome c oxidase subunits in reversible mitochondrial disease. Int J Biochem Cell B. 2015;63:32–40. doi: 10.1016/j.biocel.2015.01.025. PubMed DOI

BONNE G, SEIBEL P, POSSEKEL S, MARSAC C, KADENBACH B. Expression of human cytochrome c oxidase subunits during fetal development. Eur J Biochem. 1993;217:1099–1107. doi: 10.1111/j.1432-1033.1993.tb18342.x. PubMed DOI

BRZEZINSKI P, LARSSON G. Redox-driven proton pumping by heme-copper oxidases. BBA-Bioenergetics. 2003;1605:1–13. doi: 10.1016/S0005-2728(03)00079-3. PubMed DOI

CAO X, CUI Y, ZHANG X, LOU J, ZHOU J, BEI H, WEI R. Proteomic profile of human spermatozoa in healthy and asthenozoospermic individuals. Reprod Biol Endocrin. 2018;16:4–11. doi: 10.1186/s12958-018-0334-1. PubMed DOI PMC

CARROLL J, FEARNLEY IM, SHANNON R, HIRST J, WALKER JE. Analysis of the subunit composition of complex i from bovine heart mitochondria. Mol Cell Proteomics. 2003;2:117–126. doi: 10.1074/mcp.M300014-MCP200. PubMed DOI

CIMMINO M, MION F, GOGLIA F, MINAIRE Y, GÉLOËN A. Demonstration of in vivo metabolic effects of 3,5-di-iodothyronine. J Endocrinol. 1996;149:319–325. doi: 10.1677/joe.0.1490319. PubMed DOI

COGLIATI S, CALVO E, LOUREIRO M, GUARAS AM, NIETO-ARELLANO R, GARCIA-POYATOS C, EZKURDIA I, MERCADER N, VÁZQUEZ J, ENRÍQUEZ JA. Mechanism of super-assembly of respiratory complexes III and IV. Nature. 2016;539:579–582. doi: 10.1038/nature20157. PubMed DOI

COOPER CE, BROWN GC. The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance. J Bioenerg Biomembr. 2008;40:533–539. doi: 10.1007/s10863-008-9166-6. PubMed DOI

DAHOUT-GONZALEZ C. Molecular, functional, and pathological aspects of the mitochondrial ADP/ATP carrier. Physiology. 2006;21:242–249. doi: 10.1152/physiol.00005.2006. PubMed DOI

DAS J, MILLER ST, STERN DL. Comparison of diverse protein sequences of the nuclear-encoded subunits of cytochrome c oxidase suggests conservation of structure underlies evolving functional sites. Mol Biol Evol. 2004;21:1572–1582. doi: 10.1093/molbev/msh161. PubMed DOI

DENNERLEIN S, REHLING P. Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance. J Cell Sci. 2015;128:833–837. doi: 10.1242/jcs.161729. PubMed DOI

DENNERLEIN S, WANG C, REHLING P. Plasticity of mitochondrial translation. Trends Cell Biol. 2017;27:712–721. doi: 10.1016/j.tcb.2017.05.004. PubMed DOI

ENDOU M, YOSHIDA K, HIROTA M, NAKAJIMA C, SAKAGUCHI A, KOMATSUBARA N, KURIHARA Y. Coxfa4l3, a novel mitochondrial electron transport chain Complex 4 subunit protein, switches from Coxfa4 during spermatogenesis. Mitochondrion. 2020;52:1–7. doi: 10.1016/j.mito.2020.02.003. PubMed DOI

ENRÍQUEZ JA. Supramolecular Organization of Respiratory Complexes. Annu Rev Physiol. 2016;78:533–561. doi: 10.1146/annurev-physiol-021115-105031. PubMed DOI

EWART GD, ZHANG YZ, CAPALDI RA. Switching of bovine cytochrome c oxidase subunit Via isoforms in skeletal muscle during development. Febs Lett. 1991;292:79–84. doi: 10.1016/0014-5793(91)80839-U. PubMed DOI

FONTANESI F, SOTO IC, HORN D, BARRIENTOS A. Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process. Am J Physiol-Cell Ph. 2006;291:C1129–C1147. doi: 10.1152/ajpcell.00233.2006. PubMed DOI

FORNŮSKOVÁ D, STIBŮREK L, WENCHICH L, VINSOVA K, HANSÍKOVÁ H, ZEMAN J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J. 2010;428:363–374. doi: 10.1042/BJ20091714. PubMed DOI

FUKUDA R, ZHANG H, KIM J-W, SHIMODA L, DANG CV, SEMENZA GREGG L. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129:111–122. doi: 10.1016/j.cell.2007.01.047. PubMed DOI

GALATI D, SRINIVASAN S, RAZA H, PRABU SK, KARUNAKARAN C, LOPEZ M, KALYANARAMAN B, AVADHANI NG. Role of nuclear encoded subunit Vb in the assembly and stability of cytochrome c oxidase complex: implications in mitochondrial dysfunction and ROS production. Biochem J. 2009;420:439–449. doi: 10.1042/BJ20090214. PubMed DOI PMC

GAO L, BONILLA-HENAO V, GARCIA-FLORES P, ARIAS-MAYENCO I, ORTEGA-SAENZ P, LOPEZ-BARNEO J. Gene expression analyses reveal metabolic specifications in acute O2 -sensing chemoreceptor cells. J Physiol. 2017a;595:6091–6120. doi: 10.1113/JP274684. PubMed DOI PMC

GAO S-P, SUN H-F, FU W-Y, LI L-D, ZHAO Y, CHEN M-T, JIN W. High expression of COX5B is associated with poor prognosis in breast cancer. Future Oncol. 2017b;13:1711–1719. doi: 10.2217/fon-2017-0058. PubMed DOI

GOLDBERG A, WILDMAN DE, SCHMIDT TR, HU M, GOODMAN M, WEISS ML, GROSSMAN LI. Adaptive evolution of cytochrome c oxidase subunit VIII in anthropoid primates. P Natl Acad Sci USA. 2003;100:5873–5878. doi: 10.1073/pnas.0931463100. PubMed DOI PMC

GROSSMAN LI, PURANDARE N, ARSHAD R, GLADYCK S, SOMAYAJULU M, HUTTEMANN M, ARAS S. MNRR1, a biorganellar regulator of mitochondria. Oxid Med Cell Longev. 2017;2017:6739236. doi: 10.1155/2017/6739236. PubMed DOI PMC

GUO R, ZONG S, WU M, GU J, YANG M. Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell. 2017;170:1247–1257.e1212. doi: 10.1016/j.cell.2017.07.050. PubMed DOI

HALLMANN K, KUDIN AP, ZSURKA G, KORNBLUM C, REIMANN J, STÜVE B, WALTZ S, HATTINGEN E, THIELE H, NÜRNBERG P, RÜB C, VOOS W, KOPATZ J, NEUMANN H, KUNZ WS. Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain. 2016;139:338–345. doi: 10.1093/brain/awv357. PubMed DOI

HAYASHI T, ASANO Y, SHINTANI Y, AOYAMA H, KIOKA H, TSUKAMOTO O, HIKITA M, SHINZAWA-ITOH K, TAKAFUJI K, HIGO S, KATO H, YAMAZAKI S, MATSUOKA K, NAKANO A, ASANUMA H, ASAKURA M, MINAMINO T, GOTO Y-I, OGURA T, KITAKAZE M, KOMURO I, SAKATA Y, TSUKIHARA T, YOSHIKAWA S, TAKASHIMA S. Higd1a is a positive regulator of cytochrome c oxidase. P Natl Acad Sci USA. 2015;112:1553–1558. doi: 10.1073/pnas.1419767112. PubMed DOI PMC

HIRST J. Open questions: respiratory chain supercomplexes-why are they there and what do they do? BMC Biol. 2018;16:111. doi: 10.1186/s12915-018-0577-5. PubMed DOI PMC

HOCK DH, RELJIC B, ANG CS, MUELLNER-WONG L, MOUNTFORD HS, COMPTON AG, RYAN MT, THORBURN DR, STROUD DA. HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV. Mol Cell Proteomics. 2020;19:1145–1160. doi: 10.1074/mcp.RA120.002076. PubMed DOI PMC

HOSLER JP. The influence of subunit III of cytochrome c oxidase on the D pathway, the proton exit pathway and mechanism-based inactivation in subunit I. BBA-Bioenergetics. 2004;1655:332–339. doi: 10.1016/j.bbabio.2003.06.009. PubMed DOI

HU T, XI J. Identification of COX5B as a novel biomarker in high-grade glioma patients. Oncotargets Ther. 2017;10:5463–5470. doi: 10.2147/OTT.S139243. PubMed DOI PMC

HÜTTEMANN M, JARADAT S, GROSSMAN LI. Cytochrome c oxidase of mammals contains a testes-specific isoform of subunit VIb - the counterpart to testes-specific cytochrome c? Mol Reprod Dev. 2003;66:8–16. doi: 10.1002/mrd.10327. PubMed DOI

HÜTTEMANN M, KADENBACH B, GROSSMAN LI. Mammalian subunit IV isoforms of cytochrome c oxidase. Gene. 2001;267:111–123. doi: 10.1016/S0378-1119(01)00385-7. PubMed DOI

HÜTTEMANN M, KLEWER S, LEE I, PECINOVA A, PECINA P, LIU J, LEE M, DOAN JW, LARSON D, SLACK E. Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy. Mitochondrion. 2012;12:294–304. doi: 10.1016/j.mito.2011.11.002. PubMed DOI PMC

HÜTTEMANN M, LEE I, LIU J, GROSSMAN LI. Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element. FEBS J. 2007;274:5737–5748. doi: 10.1111/j.1742-4658.2007.06093.x. PubMed DOI

CHANCE B, WILLIAMS GR. A method for the localization of sites for oxidative phosphorylation. Nature. 1955;176:250–254. doi: 10.1038/176250a0. PubMed DOI

CHAZOTTE B, HACKENBROCK CR. Lateral diffusion as a rate-limiting step in ubiquinone-mediated mitochondrial electron transport. J Biol Chem. 1989;264:4978–4985. PubMed

CHEN W-L, KUO K-T, CHOU T-Y, CHEN C-L, WANG C-H, WEI Y-H, WANG L-S. The role of cytochrome c oxidase subunit Va in non-small cell lung carcinoma cells: association with migration, invasion and prediction of distant metastasis. BMC Cancer. 2012a;12:1–13. doi: 10.1186/1471-2407-12-273. PubMed DOI PMC

CHEN YC, TAYLOR EB, DEPHOURE N, HEO JM, TONHATO A, PAPANDREOU I, NATH N, DENKO NC, GYGI SP, RUTTER J. Identification of a protein mediating respiratory supercomplex stability. Cell Metab. 2012b;15:348–360. doi: 10.1016/j.cmet.2012.02.006. PubMed DOI PMC

CHEN ZX, PERVAIZ S. Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Differ. 2010;17:408–420. doi: 10.1038/cdd.2009.132. PubMed DOI

IMAI Y, MENG H, SHIBA-FUKUSHIMA K, HATTORI N. Twin CHCH Proteins, CHCHD2, and CHCHD10: key molecules of Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Int J Mol Sci. 2019;20 doi: 10.3390/ijms20040908. PubMed DOI PMC

IMAI M, SAIO T, KUMETA H, UCHIDA T, INAGAKI F, ISHIMORI K. Investigation of the redox-dependent modulation of structure and dynamics in human cytochrome c. Biochem Biophys Res Commun. 2016;469:978–984. doi: 10.1016/j.bbrc.2015.12.079. PubMed DOI

INDRIERI A, RAHDEN VAV, TIRANTI V, MORLEO M, IACONIS D, TAMMARO R, AMATO ID, CONTE I, MAYSTADT I, DEMUTH S, ZVULUNOV A, KUTSCHE K, ZEVIANI M, FRANCO B. Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease. Am J Hum Genet. 2012;91:942–949. doi: 10.1016/j.ajhg.2012.09.016. PubMed DOI PMC

KADENBACH B, BARTH J, AKGÜN R, FREUND R, LINDER D, POSSEKEL S. Regulation of mitochondrial energy generation in health and disease. Biochim Biophys Acta. 1995;1271:103–109. doi: 10.1016/0925-4439(95)00016-W. PubMed DOI

KADENBACH B, HÜTTEMANN M. The subunit composition and function of mammalian cytochrome c oxidase. Mitochondrion. 2015;24:64–76. doi: 10.1016/j.mito.2015.07.002. PubMed DOI

KADENBACH B, JARAUSCH J, HARTMANN R, MERLE P. Separation of mammalian cytochrome c oxidase into 13 polypeptides by a sodium dodecyl sulfate-gel electrophoretic procedure. Anal Biochem. 1983;129:517–521. doi: 10.1016/0003-2697(83)90586-9. PubMed DOI

KAILA VRI, VERKHOVSKY MI, WIKSTRÖM M. Proton-coupled electron transfer in cytochrome oxidase. Chem Rev. 2010;110:7062–7081. doi: 10.1021/cr1002003. PubMed DOI

KHALIMONCHUK O, RÖDEL G. Biogenesis of cytochrome c oxidase. Mitochondrion. 2005;5:363–388. doi: 10.1016/j.mito.2005.08.002. PubMed DOI

KRIEG RC, KNUECHEL R, SCHIFFMANN E, LIOTTA LA, III EFP, HERRMANN PC. Mitochondrial proteome: Cancer-altered metabolism associated with cytochrome c oxidase subunit level variation. Proteomics. 2004;4:2789–2795. doi: 10.1002/pmic.200300796. PubMed DOI

KRZYZOSIAK J, McMILLAN G, MOLAN P, VISHWANATH R. Protein tyrosine phosphorylation during prolonged in vitro incubation of ejaculated bovine spermatozoa is regulated by the oxidative state of the medium 1. Biol Reprod. 2000;62:1615–1623. doi: 10.1095/biolreprod62.6.1615. PubMed DOI

LANG BF, BURGER G, O’KELLY CJ. An ancestral mitochondrial DNA resembling a eubacterial genome in miniature. Nature. 1997;387:493–497. doi: 10.1038/387493a0. PubMed DOI

LANNI A, MORENO M, LOMBARDI A, GOGLIA F, GENERALE F, II F, MEZZOCANNONE V. Calorigenic effect of diiodothyronines in the rat. J Physiol. 1996;494:831–837. doi: 10.1113/jphysiol.1996.sp021536. PubMed DOI PMC

LAPUENTE-BRUN E, MORENO-LOSHUERTOS R, ACÍN-PÉREZ R, LATORRE-PELLICER A, COLAS C, BALSA E, PERALES-CLEMENTE E, QUIRÓS PM, CALVO E, RODRIGUEZ-HERNANDEZ MA, NAVAS P, CRUZ R, CARRACEDO A, LOPEZ-OTIN C, PEREZ-MARTOS A, FERNÁNDEZ-SILVA P, FERNÁNDEZ-VIZARRA E, ENRÍQUEZ JA. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science. 2013;340:1567–1570. doi: 10.1126/science.1230381. PubMed DOI

LAZAROU M, SMITH SM, THORBURN DR, RYAN MT, McKENZIE M. Assembly of nuclear DNA-encoded subunits into mitochondrial complex IV, and their preferential integration into supercomplex forms in patient mitochondria. FEBS J. 2009;276:6701–6713. doi: 10.1111/j.1742-4658.2009.07384.x. PubMed DOI

LEE I, BENDER E, KADENBACH B. Control of mitochondrial membrane potential and ROS formation by reversible phosphorylation of cytochrome c oxidase. Mol Cell Biochem. 2002;234:63–70. doi: 10.1007/978-1-4615-1087-1_7. PubMed DOI

LEE I, KADENBACH B. Palmitate decreases proton pumping of liver-type cytochrome c oxidase. Eur J Biochem. 2001;268:6329–6334. doi: 10.1046/j.0014-2956.2001.02602.x. PubMed DOI

LEE I, SALOMON AR, FICARRO S, MATHES I, LOTTSPEICH F, GROSSMAN LI, HU M. cAMP-dependent tyrosine phosphorylation of subunit i inhibits cytochrome c oxidase activity. J Biol Chem. 2005;280:6094–6100. doi: 10.1074/jbc.M411335200. PubMed DOI

LETTS JA, FIEDORCZUK K, SAZANOV LA. The architecture of respiratory supercomplexes. Nature. 2016;537:644–648. doi: 10.1038/nature19774. PubMed DOI

LETTS JA, SAZANOV LA. Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain. Nature Structural and Molecular Biology. 2017;24:800–808. doi: 10.1038/nsmb.3460. PubMed DOI

LIANG H. A rare polymorphism of the COX7B2 gene in a Cantonese family with nasopharyngeal carcinoma. Sci China Ser C. 2004;47:449. doi: 10.1360/03yc0037. PubMed DOI

LINDER D, FREUND R, KADENBACH B. Species-specific expression of cytochrome c oxidase isozymes. Comp Biochem Phys B. 1995;112:461–469. doi: 10.1016/0305-0491(95)00093-3. PubMed DOI

LITTLE AG, KOCHA KM, LOUGHEED SC, MOYES CD. Evolution of the nuclear-encoded cytochrome oxidase subunits in vertebrates. Physiol Genomics. 2010;42:76–84. doi: 10.1152/physiolgenomics.00015.2010. PubMed DOI

LUDWIG B, BENDER E, ARNOLD S, HÜTTEMANN M, LEE I, KADENBACH B. Cytochrome c oxidase and the regulation of oxidative phosphorylation. ChemBioChem. 2001;2:392–403. doi: 10.1002/1439-7633(20010601)2:6<392::AID-CBIC392>3.0.CO;2-N. PubMed DOI

MASSA V, FERNÁNDEZ-VIZARRA E, ALSHAHWAN S, BAKHSH E, GOFFRINI P, FERRERO I, MEREGHETTI P, ADAMO PD, GASPARINI P, ZEVIANI M. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet. 2008;82:1281–1289. doi: 10.1016/j.ajhg.2008.05.002. PubMed DOI PMC

McEWEN JE, KO C, KLOECKNER-GRUISSEM B, POYTON RO. Nuclear functions required for cytochrome c oxidase biogenesis in saccharomyces cerevisiae. J Biol Chem. 1986;261:11872–11879. PubMed

MICK DU, DENNERLEIN S, WIESE H, REINHOLD R, PACHEU-GRAU D, LORENZI I, SASARMAN F, WERAARPACHAI W, SHOUBRIDGE EA, WARSCHEID B, REHLING P. MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. Cell. 2012;151:1528–1541. doi: 10.1016/j.cell.2012.11.053. PubMed DOI

MILENKOVIC D, BLAZA JN, LARSSON NG, HIRST J. The enigma of the respiratory chain supercomplex. Cell Metab. 2017;25:765–776. doi: 10.1016/j.cmet.2017.03.009. PubMed DOI

MILLETT F, De JONG C, PAULSON L, CAPALDI RA. Identification of specific carboxylate groups on cytochrome c oxidase that are involved in binding cytochrome c. Biochemistry. 1983;22:546–552. doi: 10.1021/bi00272a004. PubMed DOI

MORENO-DOMINGUEZ A, ORTEGA-SAENZ P, GAO L, COLINAS O, GARCIA-FLORES P, BONILLA-HENAO V, ARAGONES J, HUTTEMANN M, GROSSMAN LI, WEISSMANN N, SOMMER N, LOPEZ-BARNEO J. Acute O2 sensing through HIF2alpha-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors. Sci Signal. 2019 doi: 10.1126/scisignal.aay9452. PubMed DOI

MOURIER A, MATIC S, RUZZENENTE B, LARSSON NG, MILENKOVIC D. The respiratory Chain supercomplex organization is independent of COX7A2L isoforms. Cell Metab. 2014;20:1069–1075. doi: 10.1016/j.cmet.2014.11.005. PubMed DOI PMC

NIJTMANS LGJ, TAANMAN J-W, MUIJSERS AO, SPEIJER D, BOGERT CVANDEN. Assembly of cytochrome c oxidase in cultured human cells. Eur J Biochem. 1998;254:389–394. doi: 10.1046/j.1432-1327.1998.2540389.x. PubMed DOI

PAJUELO REGUERA D, CUNATOVA K, VRBACKY M, PECINOVA A, HOUSTEK J, MRACEK T, PECINA P. Cytochrome c oxidase subunit 4 isoform exchange results in modulation of oxygen affinity. Cells. 2020:9. doi: 10.3390/cells9020443. PubMed DOI PMC

PANNALA VR, CAMARA AK, DASH RK. Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition. J Appl Physiol (1985) 2016;121:1196–1207. doi: 10.1152/japplphysiol.00524.2016. PubMed DOI PMC

PECINA P, HOUŠŤKOVÁ H, HANSÍKOVÁ H, ZEMAN J, HOUŠTĚK J. Genetic defects of cytochrome c oxidase assembly. Physiol Res. 2004;53:S213–S223. PubMed

PIERRON D, WILDMAN DE, HÜTTEMANN M, MARKONDAPATNAIKUNI GC. Cytochrome c oxidase: Evolution of control via nuclear subunit addition. BBA-Bioenergetics. 2012;1817:590–597. doi: 10.1016/j.bbabio.2011.07.007. PubMed DOI PMC

PILLAI NR, ALDHAHERI NS, GHOSH R, LIM J, STREFF H, NAYAK A, GRAHAM BH, HANCHARD NA, ELSEA SH, SCAGLIA F. Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures. Am J Med Genet A. 2019:1–6. doi: 10.1002/ajmg.a.61288. PubMed DOI

PITCEATHLY RDS, RAHMAN S, WEDATILAKE Y, POLKE JM, CIRAK S, FOLEY AR, SAILER A, HURLES ME, STALKER J, HARGREAVES I, WOODWARD CE, SWEENEY MG, MUNTONI F, HOULDEN H, TAANMAN J-W, HANNA M. NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. Cell Reports. 2013;3:1795–1805. doi: 10.1016/j.celrep.2013.05.005. PubMed DOI PMC

PITCEATHLY RDS, TAANMAN J-W. NDUFA4 (Renamed COXFA4) Is a cytochrome -c oxidase subunit. Trends Endocrin Met. 2018;29:452–454. doi: 10.1016/j.tem.2018.03.009. PubMed DOI

RADFORD NB, WAN B, RICHMAN A, SZCZEPANIAK LS, LI J-L, LI K, PFEIFFER K, SCHA H, GARRY DJ, MOREADITH RW, NINA B, WAN B, RICHMAN A, SZCZEPANIAK S, LI J-L, LI K, PFEIFFER K, GARRY DJ, RANDALL W. Cardiac dysfunction in mice lacking cytochrome- c oxidase subunit VIaH. Am J Physiol-Heart C. 2002;282:726–733. doi: 10.1152/ajpheart.00308.2001. PubMed DOI

RAK M, BENIT P, CHRETIEN D, BOUCHEREAU J, SCHIFF M, EL-KHOURY R, TZAGOLOFF A, RUSTIN P. Mitochondrial cytochrome c oxidase deficiency. Clin Sci. 2016;130:393–407. doi: 10.1042/CS20150707. PubMed DOI PMC

RICHTER-DENNERLEIN R, OELJEKLAUS S, LORENZI I, RONSÖR C, BARETH B, SCHENDZIELORZ AB, WANG C, WARSCHEID B, REHLING P, DENNERLEIN S. Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein. Cell. 2016;167:471–483.e410. doi: 10.1016/j.cell.2016.09.003. PubMed DOI PMC

SAMPSON V, ALLEYNE T. Cytochrome c/cytochrome c oxidase interaction - Direct structural evidence for conformational changes during enzyme turnover. Eur J Biochem. 2001;268:6534–6544. doi: 10.1046/j.0014-2956.2001.02608.x. PubMed DOI

SHARMA V, ALA-VANNESLUOMA P, VATTULAINEN I, WIKSTRÖM M, RÓG T. Role of subunit III and its lipids in the molecular mechanism of cytochrome c oxidase. BBA-Bioenergetics. 2015;1847:690–697. doi: 10.1016/j.bbabio.2015.04.007. PubMed DOI

SHTEYER E, SAADA A, SHAAG A, AL-HIJAWI FA, KIDESS R, REVEL-VILK S, ELPELEG O. Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene. Am J Hum Genet. 2009;84:412–417. doi: 10.1016/j.ajhg.2009.02.006. PubMed DOI PMC

SCHÄGGER H, PFEIFFER K. Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J. 2000;19:1777–1783. doi: 10.1093/emboj/19.8.1777. PubMed DOI PMC

SCHMIDT TR, GOODMAN M, GROSSMAN LI. Molecular evolution of the COX7A gene family in primates. Mol Biol Evol. 1999;16:619–626. doi: 10.1093/oxfordjournals.molbev.a026144. PubMed DOI

SOMMER N, HÜTTEMANN M, PAK O, SCHEIBE S, KNOEPP F, SINKLER C, MALCZYK M, GIERHARDT M, ESFANDIARY A, KRAUT S, JONAS F, VEITH C, ARAS S, SYDYKOV A, ALEBRAHIMDEHKORDI N, GIEHL K, HECKER M, BRANDES RP, SEEGER W, GRIMMINGER F, GHOFRANI HA, SCHERMULY RT, GROSSMAN LI, WEISSMANN N. Mitochondrial complex IV subunit 4 isoform 2 is essential for acute pulmonary oxygen sensing. Circ Res. 2017;121:424–438. doi: 10.1161/CIRCRESAHA.116.310482. PubMed DOI PMC

STIBŮREK L, ZEMAN J. Assembly factors and ATP-dependent proteases in cytochrome c oxidase biogenesis. BBA-Bioenergetics. 2010;1797:1149–1158. doi: 10.1016/j.bbabio.2010.04.006. PubMed DOI

STROGOLOVA V, FURNESS A, ROBB-MCGRATH M, GARLICH J, STUART RA. Rcf1 and Rcf2, members of the hypoxia-induced gene 1 protein family, are critical components of the mitochondrial cytochrome bc1-cytochrome c oxidase supercomplex. Mol Cell Biol. 2012;32:1363–1373. doi: 10.1128/MCB.06369-11. PubMed DOI PMC

SZKLARCZYK R, HUYNEN MA. Mosaic origin of the mitochondrial proteome. Proteomics. 2010;10:4012–4024. doi: 10.1002/pmic.201000329. PubMed DOI

TAMIYA G, MAKINO S, HAYASHI M, ABE A, NUMAKURA C, UEKI M, TANAKA A, ITO C, TOSHIMORI K, OGAWA N, TERASHIMA T, MAEGAWA H, YANAGISAWA D, TOOYAMA I, TADA M, ONODERA O, HAYASAKA K. A mutation of COX6A1 causes a recessive axonal or mixed form of charcot-marie-tooth disease. Am J Hum Genet. 2014;95:294–300. doi: 10.1016/j.ajhg.2014.07.013. PubMed DOI PMC

TIMON-GOMEZ A, GARLICH J, STUART RA, UGALDE C, BARRIENTOS A. Distinct roles of mitochondrial higd1a and higd2a in respiratory complex and supercomplex biogenesis. Cell Reports. 2020;31:107607. doi: 10.1016/j.celrep.2020.107607. PubMed DOI

TIMÓN-GÓMEZ A, NÝVLTOVÁ E, ABRIATA LA, VILA AJ, HOSLER J, BARRIENTOS A. Mitochondrial cytochrome c oxidase biogenesis: recent developments. Semin Cell Dev Biol. 2017;76:163–178. doi: 10.1016/j.semcdb.2017.08.055. PubMed DOI PMC

TSUKIHARA T, AOYAMA H, TOMIZAKI T, YAMAGUCHI H, NAKASHIMA R, YAONO R, YOSHIKAWA S. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science. 1996;272:1136–1144. doi: 10.1126/science.272.5265.1136. PubMed DOI

TZAGOLOFF A, DIECKMANN CL. PET Genes of Saccharomyces cerevisiae. Microbiol Rev. 1990;54:211–225. doi: 10.1128/MMBR.54.3.211-225.1990. PubMed DOI PMC

VIDONI S, HARBOUR ME, GUERRERO-CASTILLO S, SIGNES A, DING S, FEARNLEY IM, TAYLOR RW, TIRANTI V, ARNOLD S, FERNÁNDEZ-VIZARRA E, ZEVIANI M. MR-1S Interacts with PET100 and PET117 in module-based assembly of human cytochrome c oxidase. Cell Reports. 2017;18:1727–1738. doi: 10.1016/j.celrep.2017.01.044. PubMed DOI

WEISHAUPT A, KADENBACH B. Selective removal of subunit VIb increases the activity of cytochrome c oxidase. Biochemistry. 1992;31:11477–11481. doi: 10.1021/bi00161a028. PubMed DOI

WILLIAMS L, VALNOT I, RUSTIN P, TAANMAN J-W. Cytochrome c oxidase subassemblies in fibroblast cultures from patients carrying mutations in COX10, SCO1, or SURF1. J Biol Chem. 2004;279:7462–7469. doi: 10.1074/jbc.M309232200. PubMed DOI

WITTIG I, SCHÄGGER H. Advantages and limitations of clear-native PAGE. Proteomics. 2005;5:4338–4346. doi: 10.1002/pmic.200500081. PubMed DOI

WU M, GU J, GUO R, HUANG Y, YANG M. Structure of mammalian respiratory supercomplex I1III2IV1. Cell. 2016;167:1598–1609.e1510. doi: 10.1016/j.cell.2016.11.012. PubMed DOI

YANG W-L, IACONO L, TANG W-M, CHIN K-V. Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Biochemistry. 1998;37:14175–14180. doi: 10.1021/bi981402a. PubMed DOI

ZHANG K, WANG G, ZHANG X, HÜTTEMANN PP, QIU Y, LIU J, MITCHELL A, LEE I, ZHANG C, LEE JS, PECINA P, WU G, YANG ZQ, HÜTTEMANN M, GROSSMAN LI. COX7AR is a stress-inducible mitochondrial COX subunit that promotes breast cancer malignancy. Sci Rep-UK. 2016;6:1–12. doi: 10.1038/srep31742. PubMed DOI PMC

ZONG S, WU M, GU J, LIU T, GUO R, YANG M. Structure of the intact 14-subunit human cytochrome c oxidase. Cell Res. 2018;28:1026–1034. doi: 10.1038/s41422-018-0071-1. PubMed DOI PMC

Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle

Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis