title: Disrupted ATP synthase activity and mitochondrial hyperpolarisation-dependent oxidative stress is associated with p66Shc phosphorylation in fibroblasts of NARP patients.
abstract: p66Shc is an adaptor protein involved in cell proliferation and differentiation that undergoes phosphorylation at Ser36 in response to oxidative stimuli, consequently inducing a burst of reactive oxygen species (ROS), mitochondrial disruption and apoptosis. Its role during several pathologies suggests that p66Shc mitochondrial signalling can perpetuate a primary mitochondrial defect, thus contributing to the pathophysiology of that condition. Here, we show that in the fibroblasts of neuropathy, ataxia and retinitis pigmentosa (NARP) patients, the p66Shc phosphorylation pathway is significantly induced in response to intracellular oxidative stress related to disrupted ATP synthase activity and mitochondrial membrane hyperpolarisation. We postulate that the increased phosphorylation of p66Shc at Ser36 is partially responsible for further increasing ROS production, resulting in oxidative damage of proteins. Oxidative stress and p66Shc phosphorylation at Ser36 may be mitigated by antioxidant administration or the use of a p66Shc phosphorylation inhibitor. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
authors.affiliation: Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lebiedzinska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Karkucinska-Wieckowska
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtala
authors.forename: Jan M
authors.initials: JM
authors.lastname: Suski
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Szabadkai
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wilczynski
authors.forename: Jakub
authors.initials: J
authors.lastname: Wlodarczyk
authors.forename: Catia V
authors.initials: CV
authors.lastname: Diogo
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.forename: Jan
authors.initials: J
authors.lastname: Tauber
authors.forename: Petr
authors.initials: P
authors.lastname: Ježek
authors.forename: Maciej
authors.initials: M
authors.lastname: Pronicki
authors.forename: Jerzy
authors.initials: J
authors.lastname: Duszynski
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Mariusz R
authors.initials: MR
authors.lastname: Wieckowski
mesh_terms: D017209:Apoptosis / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D025261:Mitochondrial Proton-Translocating ATPases