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

Formosa, Luke E.; Reljić, Boris; Sharpe, Alice J.; Muellner-Wong, Linden; Stroud, David A.; Ryan, Michael

doi:10.1101/2020.09.18.303255

Cited by 6 publications

(7 citation statements)

References 57 publications

(107 reference statements)

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“…Being that TMEM126A is a paralog of TMEM126B, it was suggested that the former could compensate for the loss of function of the latter [52]. However, recent data point out to a role for TMEM16A as an assembly factor associated with the ND4-module [87,88]. NDUFAF2 (B17.2L or NDU-FA12L) was mutated in patients showing either generic encephalopathic syndromes or Leigh syndrome [89][90][91][92].…”

Section: Mutations In Factors and Chaperones Regulating Complex I Assemblymentioning

confidence: 99%

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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Section: Mutations In Factors and Chaperones Regulating Complex I Assemblymentioning

confidence: 99%

Mitochondrial disorders of the OXPHOS system

2020

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“…In particular, the rare recessive form of optic neuropathy associated with mutations in the Transmembrane Protein 126A ( TMEM126A ) gene ( OPA7 ), sometimes leading to additional neurological features (auditory neuropathy, sensorimotor axonal neuropathy, mild hypertrophic cardiomyopathy), was documented to lead to partial deficiency of complex I in one patient [ 54 ]. Concordantly, two recent studies identified TMEM126A as a factor necessary for the correct complex I assembly [ 55 , 56 ]. Furthermore, another recessive form of isolated or syndromic optic neuropathy associated with mutations in the Reticulon 4 Interacting Protein 1 ( RTN4IP1 ) gene ( OPA10 ) has been reported to present with a combined defect of complex I and IV [ 57 ], but also with a profound complex I defect when associated with the severe phenotype [ 58 ].…”

Section: Complex I Dysfunction: the Paradigm Of Leber’s Hereditary Optic Neuropathy (Lhon)mentioning

confidence: 69%

Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Maresca

Carelli

2021

Biomolecules

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Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

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“…Data Availability. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE (63) partner repository (https://www.ebi.ac.uk/pride/archive) with the dataset identifier PXD023136 (64).…”

Section: Methodsmentioning

confidence: 99%

Optic atrophy–associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I

Formosa

Reljić

Sharpe

et al. 2021

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

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Mitochondrial disease is a debilitating condition with a diverse genetic etiology. 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-labeling interaction studies reveal that TMEM126A associates with the newly synthesized mitochondrial DNA (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. In addition, we find that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I.

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

Cited by 6 publications

References 57 publications

Mitochondrial disorders of the OXPHOS system

Mitochondrial disorders of the OXPHOS system

Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Optic atrophy–associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I

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