Human COX7A2L Regulates Complex III Biogenesis and Promotes Supercomplex Organization Remodeling without Affecting Mitochondrial Bioenergetics

Lobo-Jarne, Teresa; Nývltová, Eva; Pérez-Pérez, Rafael; Timón‐Gómez, Alba; Molinié, Thibaut; Choi, Austin; Mourier, Arnaud; Fontanesi, Flavia; Ugalde, Cristina; Barrientos, Antoni

doi:10.1016/j.celrep.2018.10.058

Cited by 60 publications

(74 citation statements)

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“…Our conclusion is that the impact of HIGD2A on the supercomplex is a pleotropic effect due to defective complex IV assembly. The intersection of the latter assembly steps of complexes I, III and IV with supercomplex formation [8,[16][17][18]20,23] is also a major factor to be considered in interpretation of the results from ours and other studies. We detected subunits of complexes I, III and IV as well as assembly factors for complexes I and IV in our HIGD2A FLAG affinity enrichment experiment ( Fig.…”

Section: Discussionmentioning

confidence: 75%

“…The most well-known example is COX7A2L (SCAFI), which was originally found within the supercomplex but not holo complex IV [6]. A role of COX7A2L in supercomplex assembly has been disputed by multiple groups [18][19][20][21][22][23] and the protein is now understood to act as a checkpoint for assembly of complex III into the supercomplex [23]. Another example is UQCC3 (C11orf83), which is an assembly factor suggested to stabilize the CIII2/IV form of the supercomplex [57].…”

Section: Discussionmentioning

confidence: 99%

“…To assess the assembly of complex IV and supercomplexes we performed Blue Native (BN)-PAGE. When using the weak nonionic detergent digitonin, BN-PAGE is capable of resolving stalled complex IV assembly intermediates, holo complex IV and multiple high-order supercomplex structures [10,20,23,35,36]. As can be seen in Fig.…”

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

confidence: 99%

“…A mouse strain harboring a truncated form of the protein lacked some forms of the supercomplexes and exhibited altered mitochondrial respiration, leading the authors to suggest the protein is required for supercomplex stability [6]. Several studies have disputed this finding [18][19][20][21][22][23] and it is now understood that COX7A2L plays a role as a checkpoint for assembly of CIII2 into the supercomplex [23], a result that explains the differences in supercomplex distribution observed in mitochondria lacking full length COX7A2L. Yeast (S. cerevisiae) homologs of HIGD2A (Rcf1 and Rcf2) belong to the hypoxia inducible gene 1 domain containing (HIGD) family and were originally suggested to be required for assembly and stability of the yeast CIII2/IV supercomplex [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hock

Reljić

et al. 2019

Preprint

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“…No specific phenotype has yet been ascribed to SCAF1 111 mouse strains, and this has contributed to the arguments against a physiological role for the super-assembly of CIII and CIV. Furthermore, a recent study performed in cultured cells suggested that the ablation of SCAF1 has no bioenergetic relevance 17 , a conclusion that was refuted by the demonstration that SCAF1 was critical for the cellular metabolic adaptation to the increase in energy demands associated with endoplasmic reticulum stress and nutrient starvation 18 . Controversy over the bioenergetic role of CIII and CIV super-assembly thus remains, and a physiological role has not been yet described.…”

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confidence: 99%

Respiratory supercomplexes provide metabolic efficiency in zebrafish

García-Poyatos

Cogliati

Hernansanz-Agustín

et al. 2019

Preprint

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or J.A. 13 Enríquez (jaenriquez@cnic.es). 14 15 16 17The oxidative phosphorylation (OXPHOS) system is a dynamic system in which the 18 respiratory complexes coexist with super-assembled quaternary structures called 19 supercomplexes (SCs). The physiological role of SCs is still disputed. Here we used zebrafish to 20 study the relevance of respiratory SCs. We combined immunodetection analysis and deep data-21 independent proteomics to characterize these structures and found similar SCs to those 22 described in mice, as well as novel SCs including III2+IV2, I+IV and I+III2+IV2. To study the 23 physiological role of SCs, we generated two null allele zebrafish lines for supercomplex 24 assembly factor 1 (SCAF1). SCAF1 -/fish displayed altered OXPHOS activity due to the 25 disrupted interaction of complex III and IV. SCAF1 -/fish were smaller in size, and showed 26 abnormal fat deposition and decreased female fertility. These physiological phenotypes were 27 rescued by doubling the food supply, which correlated with improved bioenergetics and 28 alterations in the metabolic gene expression program. These results reveal that SC assembly by 29 SCAF1 modulates OXPHOS efficiency and allows for the optimization of metabolic resources. 30In the last two years, the focus of investigation on the structure of the mitochondrial electron 31 transport chain (ETC) has shifted from the dispute over the existence of supercomplexes (SCs) to 32 their putative functional role. In mammals, the best understood mechanism of respiratory complex 33 super-assembly is the interaction between complexes III (CIII) and IV (CIV) mediated by 34 supercomplex assembly factor 1 (SCAF1/COX7A2L) 1 . The carboxy-terminus of SCAF1 is very 35 similar to that of the CIV subunit COX7A2 and replaces it in the subset of CIV molecules that super-36 assemble with CIII 2 . After some initial doubts 3 , which were later dispelled 4,5 , the role of SCAF1 in 37 the super-assembly of CIII and CIV is now generally accepted 2 . The process of super-assembly 38 between CI and CIII and CI and CIV to form the respirasome is unknown, but the proposed existence 39 of I+IV SCs 6 suggests that CI-CIII and CI-CIV super-assembly might occur independent from CIII 40 and CIV assembly 7,8 . So far, the interaction between CI and CIV has been mostly studied in SCs 41 containing CI, CIII and CIV (also named respirasomes). Several forms of respirasomes (I+III2+IV) 42 migrate closely together in blue native gel electrophoresis (BNGE), although the reason for their 43 SCAF1 protein (SCAF1 111 ) lacking two amino acids as compared with functional SCAF1 63 (SCAF1 113 ). SCAF1 111 mice do not assemble III2+IV and the formation of respirasomes is affected 1,2 . 64No specific phenotype has yet been ascribed to SCAF1 111 mouse strains, and this has contributed to 65 the arguments against a physiological role for the super-assembly of CIII and CIV. Furthermore, a 66 recent study performed in cultured cells suggested that the ablation of SCAF1 has no bioenergetic 67 relevance 17 , a conclusio...

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Mitochondrial disorders of the OXPHOS system

2020

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Mitochondrial disorders are amongst the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase (also called complex V). The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by complex V to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

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Human COX7A2L Regulates Complex III Biogenesis and Promotes Supercomplex Organization Remodeling without Affecting Mitochondrial Bioenergetics

Cited by 60 publications

References 49 publications

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

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

Respiratory supercomplexes provide metabolic efficiency in zebrafish

Mitochondrial disorders of the OXPHOS system

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