Assembly of mammalian oxidative phosphorylation complexes I–V and supercomplexes

Signes, Alba; Fernández-Vizarra, Erika

doi:10.1042/ebc20170098

Cited by 231 publications

(240 citation statements)

References 204 publications

(208 reference statements)

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“…This finding was surprising since MT-CYB, the only mtDNAencoded subunit of cIII 2 , has consistently been considered as the "seed" around which the rest of cIII 2 builds up, assuming that no intermediates could be assembled independently from MT-CYB (Ndi et al, 2018). Moreover, the current cIII 2 assembly model establishes an early interaction of CYC1 with UQCRC1 and UQCRC2 (Zara et al, 2009;Signes & Fernandez-Vizarra, 2018). Our data are not compatible with this hypothesis since CYC1 accumulated in different protein structures, whereas UQCRC1 and UQCRC2, whose stability critically depends on the presence of MT-CYB, were virtually undetected.…”

Section: Discussionmentioning

confidence: 94%

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

et al. 2020

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Mitochondrial respiratory chain (MRC) enzymes associate in supercomplexes (SCs) that are structurally interdependent. This may explain why defects in a single component often produce combined enzyme deficiencies in patients. A case in point is the alleged destabilization of complex I in the absence of complex III. To clarify the structural and functional relationships between complexes, we have used comprehensive proteomic, functional, and biogenetical approaches to analyze a MT-CYB-deficient human cell line. We show that the absence of complex III blocks complex I biogenesis by preventing the incorporation of the NADH module rather than decreasing its stability. In addition, complex IV subunits appeared sequestered within complex III subassemblies, leading to defective complex IV assembly as well. Therefore, we propose that complex III is central for MRC maturation and SC formation. Our results challenge the notion that SC biogenesis requires the pre-formation of fully assembled individual complexes. In contrast, they support a cooperative-assembly model in which the main role of complex III in SCs is to provide a structural and functional platform for the completion of overall MRC biogenesis.

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Section: Discussionmentioning

confidence: 94%

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

et al. 2020

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“…These assembly factors represent a functionally heterogeneous group of proteins that fulfill different and mostly complexspecific functions [7][8][9][10]. These assembly factors represent a functionally heterogeneous group of proteins that fulfill different and mostly complexspecific functions [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…It is becoming increasingly clear that assembly of the oxidative phosphorylation system complexes occurs in a modular fashion [7]. In recent analyses, the biogenesis of the NADH:coenzyme Q oxidoreductase (complex I) was mapped in detail by defining assembly intermediates with mass spectrometric approaches [16,17].…”

Section: Introductionmentioning

confidence: 99%

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

et al. 2019

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The mitochondrial genome encodes for thirteen core subunits of the oxidative phosphorylation system. These proteins assemble with imported proteins in a modular manner into stoichiometric enzyme complexes. Assembly factors assist in these biogenesis processes by providing co-factors or stabilizing transient assembly stages. However, how expression of the mitochondrial-encoded subunits is regulated to match the availability of nuclear-encoded subunits is still unresolved. Here, we address the function of MITRAC15/COA1, a protein that participates in complex I biogenesis and complex IV biogenesis. Our analyses of a MITRAC15 knockout mutant reveal that MITRAC15 is required for translation of the mitochondrial-encoded complex I subunit ND2. We find that MITRAC15 is a constituent of a ribosome-nascent chain complex during ND2 translation. Chemical crosslinking analyses demonstrate that binding of the ND2-specific assembly factor ACAD9 to the ND2 polypeptide occurs at the C-terminus and thus downstream of MITRAC15. Our analyses demonstrate that expression of the founder subunit ND2 of complex I undergoes regulation. Moreover, a ribosome-nascent chain complex with MITRAC15 is at the heart of this process.

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“…Other complex IV subunits were detected but found not to be significantly altered relative to control cells. HIGD2A KO mitochondria also contained significantly increased levels of complex IV assembly factors COA4, COA6, COA7, CMC2 and COX11 [9,16]. In contrast our, analysis of HIGD1A KO mitochondria revealed a significant reduction in the levels of a different cohort of complex IV subunits; COX1 (MT-CO1), COX4 and COX5A, as well as assembly factors SCO2 and COX18 ( Fig.…”

Section: Higd2a Stabilizes the Cox3 Module Of Complex IVmentioning

confidence: 57%

“…We also observed changes in supercomplex distribution, with a shift toward the CI/III2 assembly lacking complex IV (compare lanes 1,2, and 2,5). Additionally, HIGD2A KO [9,16,36]. Strikingly, no signal was observed for COX3 module subunit COX6A1, either in accumulated intermediates or mature complex IV assemblies ( Fig.…”

Section: Loss Of Higd2a Leads To Defective Assembly Of Complex IVmentioning

confidence: 92%

HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV

Hock

Reljić

et al. 2019

Preprint

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AbstractAssembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the membrane insertion of subunits, attachment of co-factors, and stabilization of assembly intermediates. The major fraction of complexes I, III and IV are present together in large molecular structures known as respiratory chain supercomplexes. A number of assembly factors have been proposed as required for supercomplex assembly, including the hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines and extensive steady state, translation and affinity enrichment proteomics techniques we show that loss of HIGD2A leads to defects in the de novo biogenesis of mtDNA-encoded COX3, subsequent accumulation of complex IV intermediates and turnover of COX3 partner proteins. Deletion of HIGD2A also leads to defective complex IV activity. The impact of HIGD2A loss on complex IV was not altered by growth under hypoxic conditions, consistent with its role being in basal complex IV assembly. While in the absence of HIGD2A we show that mitochondria do contain an altered supercomplex assembly, we demonstrate it to harbor a crippled complex IV lacking COX3. Our results redefine HIGD2A as a classical assembly factor required for building the COX3 module of complex IV.

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Assembly of mammalian oxidative phosphorylation complexes I–V and supercomplexes

Cited by 231 publications

References 204 publications

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

Respiratory supercomplexes act as a platform for complex III ‐mediated maturation of human mitochondrial complexes I and IV

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV

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