TMEM70 functions in the assembly of complexes I and V

Sánchez‐Caballero, Laura; Elurbe, Dei M.; Baertling, Fabian; Guerrero–Castillo, Sergio; Brand, Mariël van den; Strien, Joeri van; Dam, Teunis J. P. van; Rodenburg, Richard J.; Brandt, Ulrich; Huynen, Martijn; Nijtmans, Leo

doi:10.1016/j.bbabio.2020.148202

Cited by 36 publications

(38 citation statements)

References 61 publications

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“…Furthermore, TMEM126A Flag enriched a number of complex I assembly factors including the MCIA complex factors ECSIT and ACAD9, the ND1-module assembly factor TIMMDC1, plus the Q-module assembly factors NDUFAF3 and NDUFAF4. TMEM70, an assembly factor recently implicated in the assembly of the complex I ND4-module was also enriched (Guerrero-Castillo et al, 2017;Sánchez-Caballero et al, 2020). In agreement with previous studies (Thompson et al, 2018), we also observed that TMEM126A Flag was able to enrich the general membrane insertase for mtDNA encoded proteins, OXA1L.…”

Section: Tmem126a Associates With Complex I Subunits Assembly Factorsupporting

confidence: 91%

“…Might this ancestral protein be involved in assembly of two distinct complex I modules? Interestingly, in addition to TMEM126A and TMEM126B sharing an evolutionary origin, the transmembrane proteins TMEM70 (involved in ND4-module assembly) and TMEM186 (involved in ND2-module assembly by interacting with ND3) also share a common ancestor (Formosa et al, 2020;Guerrero-Castillo et al, 2017;Sánchez-Caballero et al, 2020). This may suggest potential symmetry involved in the assembly and integration of the ND2-and ND4-modules.…”

Section: Duplication and Specialization Of The Tmem126 Locusmentioning

confidence: 99%

“…While an MRI conducted was considered normal, the patient was reported to have moderate hypertrophic cardiomyopathy, which is a more common presentation for patients with complex I deficiency (Frazier et al, 2020;Frazier et al, 2019;Gorman et al, 2016;Hanein et al, 2009). Analysis of TMEM126A-interacting proteins revealed an association with TMEM70, a protein long known to play a role in assembly of ATP synthase through incorporation of subunit c into the complex V rotor (Kovalčíková et al, 2019;Spiegel et al, 2011), but more recently also implicated in assembly of the complex I ND4-module (PD-a intermediate) (Guerrero-Castillo et al, 2017;Sánchez-Caballero et al, 2020).…”

Section: Tmem126a Is Important For Biogenesis Of Mitochondrial Complementioning

confidence: 99%

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Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I

Formosa

Reljić

Sharpe

et al. 2020

Preprint

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Mitochondrial disease is a debilitating condition with a diverse genetic aetiology. Here, we report that TMEM126A, a protein that is mutated in patients with autosomal recessive optic atrophy, participates directly in the assembly of mitochondrial complex I. Using a combination of genome editing, interaction studies and quantitative proteomics, we find that loss of TMEM126A results in an isolated complex I deficiency and that TMEM126A interacts with a number of complex I subunits and assembly factors. Pulse-labelling interaction studies reveal that TMEM126A associates with the newly synthesised mtDNA-encoded ND4 subunit of complex I. Our findings indicate that TMEM126A is involved in the assembly of the ND4 distal membrane module of complex I. Importantly, we clarify that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I, helping to explain the differences in disease aetiology observed between these two genes.

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Section: Tmem126a Associates With Complex I Subunits Assembly Factorsupporting

confidence: 91%

Section: Duplication and Specialization Of The Tmem126 Locusmentioning

confidence: 99%

Section: Tmem126a Is Important For Biogenesis Of Mitochondrial Complementioning

confidence: 99%

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Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I

Formosa

Reljić

Sharpe

et al. 2020

Preprint

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“…According to the association of a F 1 domain with a fully assembled PS and then completed by the addition of the c 8 ring. A fourth, but related pathway of assembly of human ATP synthase has been proposed based on the mass spectrometric analysis of protein complexes fractionated by native gel electrophoresis (26). Here, a b-e-g-f subcomplex becomes incorporated into a PS complex plus subunits ATP6, ATP8, j, and k, which then associates with a F 1 -c 8 subcomplex to produce the intact ATP synthase.…”

Section: Discussionmentioning

confidence: 99%

Assembly of the peripheral stalk of ATP synthase in human mitochondria

Carroll

Ding

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The adenosine triphosphate (ATP) synthase in human mitochondria is a membrane bound assembly of 29 proteins of 18 kinds organized into F1-catalytic, peripheral stalk (PS), and c8-rotor ring modules. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, imported into the mitochondrial matrix, and assembled into the complex with the mitochondrial gene products ATP6 and ATP8. Intermediate vestigial ATPase complexes formed by disruption of nuclear genes for individual subunits provide a description of how the various domains are introduced into the enzyme. From this approach, it is evident that three alternative pathways operate to introduce the PS module (including associated membrane subunits e, f, and g). In one pathway, the PS is built up by addition to the core subunit b of membrane subunits e and g together, followed by membrane subunit f. Then this b-e-g-f complex is bound to the preformed F1-c8module by subunits OSCP and F6. The final component of the PS, subunit d, is added subsequently to form a key intermediate that accepts the two mitochondrially encoded subunits. In another route to this key intermediate, first e and g together and then f are added to a preformed F1-c8-OSCP-F6-b-d complex. A third route involves the addition of the c8-ring module to the complete F1-PS complex. The key intermediate then accepts the two mitochondrially encoded subunits, stabilized by the addition of subunit j, leading to an ATP synthase complex that is coupled to the proton motive force and capable of making ATP.

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“…The oligomerization of c subunits to form the rotor c-ring is possibly facilitated by TMEM70 to assemble with the F 1 domain [201,202]. Interestingly, TMEM70 was also linked to CI assembly, where the protein comigrated with the P D module and knockout cells accumulated Q/P p intermediates, suggesting a role in the stabilization of CI P-module during assembly [203]. The peripheral stalk consisting of b, d, F6, and OSCP subunits binds to the F 1 -c complex for stabilization, followed by association with subunits e, f, g [195][196][197].…”

Section: Complex V (F 1 F O Atp Synthase) Assemblymentioning

confidence: 99%

Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways

Tang

Thompson

Taylor

et al. 2020

IJMS

101

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The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which—given their dual-genetic control—requires tight co-regulation of two evolutionarily distinct gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors—also known as the LYRM (leucine–tyrosine–arginine motif) proteins—together with the mitochondrial acyl carrier protein (ACP)—regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.

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TMEM70 functions in the assembly of complexes I and V

Cited by 36 publications

References 61 publications

Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I

Optic Atrophy-associated TMEM126A is an assembly factor for the ND4-module of Mitochondrial Complex I

Assembly of the peripheral stalk of ATP synthase in human mitochondria

Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways

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