The mitochondrial reactive oxygen species regulator p66Shc controls PDGF-induced signaling and migration through protein tyrosine phosphatase oxidation

Frijhoff, Jeroen; Dagnell, Markus; Augsten, Martin; Beltrami, Elena; Giorgio, Marco; Östman, Arne

doi:10.1016/j.freeradbiomed.2013.12.022

Cited by 39 publications

(35 citation statements)

References 64 publications

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“…7). Although the source of ROS remains uncertain, protein phosphatase inactivation via thiol oxidation by ROS has been proposed as the mechanism for PDGFR autophosphorylation (22,33). Intriguingly, a recent study demonstrated that ROS may indirectly phosphorylate PDGFR through Src family kinases activation in the absence of PDGF (11).…”

Section: Discussionmentioning

confidence: 99%

“…1C) was shown during ATG5 knockdown. ROS can act as both an upstream and downstream mediator of PDGFR phosphorylation, and the involvement of mitochondrial ROS in PDGFR activation has been reported in cases of autophagy inhibition (22). Furthermore, PI3K/AKT activation (which is downstream of the PDGFR signaling pathway) participates in the regulation of myofibroblast differentiation (23,24).…”

Section: Atg5 Knockdown Induces Mitochondrial Ros Production Activatmentioning

confidence: 99%

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Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Kobayashi

Araya

Minagawa

et al. 2016

The Journal of Immunology

113

117

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Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Atg5 Knockdown Induces Mitochondrial Ros Production Activatmentioning

confidence: 99%

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Kobayashi

Araya

Minagawa

et al. 2016

The Journal of Immunology

113

117

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“…P66SHC protein is the largest isoform encoded by the ShcA locus, typical of vertebrates, and it sustains intracellular levels of ROS (Giorgio et al ., 2005 Gertz & Steegborn, 2010) and regulates redox signaling pathways (Frijhoff et al ., 2014), mitochondrial apoptosis (Migliaccio et al ., 2006), and aging (Trinei et al ., 2009). P66SHC null mice (p66SHC −/− ) develop normally and resulted to be protected from aging‐associated diseases, such as atherosclerosis (Martin‐Padura et al ., 2008), diabetes compliances (Menini et al ., 2007), onset (Tomilov et al ., 2011), cognitive decline (Berry et al ., 2007), and neurodegeneration (Savino et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

“…At mechanistic level, substantial evidence indicates that p66SHC regulates redox balance and mitochondrial apoptosis by suppressing ROS scavenging and increasing ROS production from plasma membrane oxidases and mitochondria where, in particular, p66SHC favors H 2 O 2 production by ETC (Gertz & Steegborn, 2010; Trinei et al ., 2013). Accordingly, p66SHC −/− tissues showed a reduced level of oxidative damage to nuclear and mitochondrial DNA (Trinei et al ., 2002), lipids (Napoli et al ., 2003), carbohydrates (Menini et al ., 2007), and proteins (Carpi et al ., 2009), which can be either unspecifically or specifically (e.g., redox‐regulated phosphatases; Frijhoff et al ., 2014) damaged by oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

2016

Self Cite

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SummaryOxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro‐oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down telomere shortening and related progeria, we have investigated the effect of p66SHC deletion, which has been shown to reduce oxidative stress and mitochondrial apoptosis, on late‐generation TERC (telomerase RNA component)‐deficient mice having short telomeres and reduced lifespan. Double mutant (TERC −/− p66SHC −/−) mice were generated, and their telomere length, fertility, and lifespan investigated in different generations. Results revealed that p66SHC deletion partially rescues sterility and weight loss, as well as organ atrophy, of TERC‐deficient mice, but not their short lifespan and telomere erosion.Therefore, our data suggest that p66SHC‐mediated oxidative stress and telomere shortening synergize in some tissues (including testes) to accelerate aging; however, early mortality of late‐generation mice seems to be independent of any link between p66SHC‐mediated oxidative stress and telomere attrition.

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“…In addition, also other transcription factors (e.g., FOXO3A, NF-kB, p53, and PGC-1α) and signaling components (e.g., c-Jun N-terminal kinase, protein tyrosine phosphatases, cysteine protease Atg4, the mitochondrial peroxiredoxins, the NLRP3 inflammasome, etc.) have been identified as targets of mitochondrial H 2 O 2 (Chandel et al, 2000a,b;Nemoto et al, 2000;Valle et al, 2005;Scherz-Shouval et al, 2007;Chiribau et al, 2008;Cox et al, 2010;Zhou et al, 2011;Chae et al, 2013;Frijhoff et al, 2014;Long et al, 2014;Marinho et al, 2014). However, although it is well known that H 2 O 2 can selectively modify proteins containing cysteine residues with a low pKa (Veal et al, 2007), the precise mechanisms by which mitochondria-derived H 2 O 2 coordinates or relays (retrograde) signaling events thereby provoking adaptive or maladaptive responses are not yet entirely clear (Forkink et al, 2010).…”

Section: Mitochondria As Redox Signaling Nodesmentioning

confidence: 99%

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

2017

Frontiers Research Topics

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The mitochondrial reactive oxygen species regulator p66Shc controls PDGF-induced signaling and migration through protein tyrosine phosphatase oxidation

Cited by 39 publications

References 64 publications

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

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