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Article

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

1
Laboratory of Bioenergetics, Institute of Physiology, Czech Academy of Sciences, 142 00 Prague, Czech Republic
2
Department of Cell Biology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
3
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK
*
Authors to whom correspondence should be addressed.
Academic Editor: Sebastian Vogt
Cells 2021, 10(2), 369; https://doi.org/10.3390/cells10020369
Received: 15 December 2020 / Revised: 2 February 2021 / Accepted: 4 February 2021 / Published: 10 February 2021
(This article belongs to the Collection Regulation of Eukaryotic Cytochrome c Oxidase)
The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependency of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process were disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII, and cIV were missing in COX4I1 knock-out (KO) due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected. We propose that attenuation of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms, which may impair biogenesis of cI. View Full-Text
Keywords: mitochondria; OXPHOS; cI; COX; cIV; COX4; knock-out; cIV assembly; complex I; biogenesis interdependency; complexome profiling; mitochondrial protein synthesis mitochondria; OXPHOS; cI; COX; cIV; COX4; knock-out; cIV assembly; complex I; biogenesis interdependency; complexome profiling; mitochondrial protein synthesis
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MDPI and ACS Style

Čunátová, K.; Reguera, D.P.; Vrbacký, M.; Fernández-Vizarra, E.; Ding, S.; Fearnley, I.M.; Zeviani, M.; Houštěk, J.; Mráček, T.; Pecina, P. Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis. Cells 2021, 10, 369. https://doi.org/10.3390/cells10020369

AMA Style

Čunátová K, Reguera DP, Vrbacký M, Fernández-Vizarra E, Ding S, Fearnley IM, Zeviani M, Houštěk J, Mráček T, Pecina P. Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis. Cells. 2021; 10(2):369. https://doi.org/10.3390/cells10020369

Chicago/Turabian Style

Čunátová, Kristýna, David P. Reguera, Marek Vrbacký, Erika Fernández-Vizarra, Shujing Ding, Ian M. Fearnley, Massimo Zeviani, Josef Houštěk, Tomáš Mráček, and Petr Pecina. 2021. "Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis" Cells 10, no. 2: 369. https://doi.org/10.3390/cells10020369

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