Biogenesis of NDUFS3-Less Complex I Indicates TMEM126A/OPA7 as an Assembly Factor of the ND4-Module

D’Angelo, Leonarda; Astro, Elisa; Luise, Monica De; Kurelac, Ivana; Ganesh, Nikkitha Umesh; Ding, Shuzhe; Fearnley, Ian M.; Zeviani, Massimo; Gasparre, Giuseppe; Porcelli, Anna Maria; Fernández-Vizarra, Erika; Iommarini, Luisa

doi:10.2139/ssrn.3731610

Cited by 1 publication

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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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