NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate

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

doi:10.1016/j.celrep.2021.109002

Cited by 23 publications

(24 citation statements)

References 62 publications

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“…Complex I was separated in its native form by blue-native PAGE 45 . Mitochondrial-enriched fractions were solubilized in 1.5 M aminocaproic acid and 50 mM Bis-Tris/HCl at pH 7 with the addition of 2.5 μg n -dodecyl β-D-maltoside (DDM)/μg mitochondrial proteins (Sigma–Aldrich, #D4641).…”

Section: Methodsmentioning

confidence: 99%

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer

Luise

Sollazzo

Lama

et al. 2022

Sci Rep

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Anticancer strategies aimed at inhibiting Complex I of the mitochondrial respiratory chain are increasingly being attempted in solid tumors, as functional oxidative phosphorylation is vital for cancer cells. Using ovarian cancer as a model, we show that a compensatory response to an energy crisis induced by Complex I genetic ablation or pharmacological inhibition is an increase in the mitochondrial biogenesis master regulator PGC1α, a pleiotropic coactivator of transcription regulating diverse biological processes within the cell. We associate this compensatory response to the increase in PGC1α target gene expression, setting the basis for the comprehension of the molecular pathways triggered by Complex I inhibition that may need attention as drawbacks before these approaches are implemented in ovarian cancer care.

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Section: Methodsmentioning

confidence: 99%

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer

Luise

Sollazzo

Lama

et al. 2022

Sci Rep

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“…As cI dysfunction is central to LHON, and prominent cI impairment is also detected in OPA1-related ADOA, it is not surprising that mutations in other cI-related genes may lead to optic atrophy when mutated. TMEM126A is one of them, recently identified as an assembly factor for ND4 subunit [ 157 , 158 ]. Mutations in TMEM126A cause recessive optic atrophy (OPA7), isolated or with sensorineural hearing loss, mostly found in families of Maghrebian ancestry due to a founder event [ 159 , 160 ].…”

Section: Rare Mitochondrial Causes Of Optic Atrophymentioning

confidence: 99%

Mitochondrial Retinopathies

Zeviani

Carelli

2021

IJMS

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The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.

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“…We genetically perturbed complex I assembly and function by knocking-out either NDUFS3 or NDUFAF7. NDUFS3 encodes NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a non-catalytic subunit of complex I necessary for complex I assembly and activity (Benit et al, 2004; D’Angelo et al, 2021) and NDUFAF7 encodes NADH:ubiquinone oxidoreductase complex assembly factor 7, a methylase necessary for the early stages of complex I assembly (Zurita Rendon et al, 2014). We targeted NDUFS3 and NDUFAF7 because these genes localize to genetic loci associated with increased risk of Alzheimer’s disease (de Rojas et al, 2021; Kunkle et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

Wynne

Ogunbona

Lane

et al. 2022

Preprint

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Mitochondria are dynamic organelles that influence cellular function through both cell- autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the inner mitochondrial membrane caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Gene editing of SLC25A family inner mitochondrial membrane transporters, as well as genetic and pharmacological disruption of copper-dependent and independent steps of electron transport chain assembly and function, caused upregulation of APOE transcript, protein, and secretion, up to 16-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC- derived human astrocytes as part of an inflammatory gene expression program. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

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NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate

Cited by 23 publications

References 62 publications

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer

Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer

Mitochondrial Retinopathies

APOE Expression and Secretion are Modulated by Mitochondrial Dysfunction

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