Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release

Berger, Alison K.; Cortese, Giuseppe P.; Amodeo, Katherine D.; Weihofen, Andreas; Letaï, Anthony; LaVoie, Matthew J.

doi:10.1093/hmg/ddp384

Cited by 76 publications

(65 citation statements)

References 48 publications

(63 reference statements)

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“…Bax and Bak are each sufficient for the apoptotic release of cytochrome c (15), but only Bax is found both in the cytosol and at the mitochondria. Thus, a primary effect of parkin on regulating mitochondrial Bax could account for both the increased cell viability demonstrated here and the altered threshold for mitochondrial cytochrome c release previously reported (10). Cytosol and mitochondrial extracts from MES and MES-Parkin cells were analyzed by Western blot (WB) for the levels of several endogenous Bcl-2 family proteins.…”

Section: Resultsmentioning

confidence: 67%

“…Parkin expression protects against caspase activation and cell death induced by stressors such as staurosporine, C2 ceramide, rotenone, and 6-OHDA (10,(12)(13)(14), and we extended these observations to include another stressor, etoposide. Neuronal dopaminergic MES and MES cells stably overexpressing human parkin (MES-Parkin) were treated with vehicle (DMSO) or etoposide (100 μM), and caspase 3/7 activity was measured at 18 h. Parental MES cells demonstrated a 100% increase in caspase 3/7 activity that was prevented by the stable over-expression of parkin (Fig.…”

Section: Resultsmentioning

confidence: 82%

“…Numerous approaches have demonstrated the influence of parkin on mitochondrial biology and apoptosis, with evidence that this effect was mediated within the cytosol (10). Bax and Bak are each sufficient for the apoptotic release of cytochrome c (15), but only Bax is found both in the cytosol and at the mitochondria.…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that parkin expression induces fundamental changes in the mitochondrial response to apoptotic stressors (10). Although these effects could be observed from isolated mitochondria, several lines of evidence have suggested that cytosolic parkin was primarily responsible.…”

mentioning

confidence: 99%

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The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

Johnson

Berger²,

Cortese³

et al. 2012

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

156

144

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Autosomal recessive loss-of-function mutations within the PARK2 gene functionally inactivate the E3 ubiquitin ligase parkin, resulting in neurodegeneration of catecholaminergic neurons and a familial form of Parkinson disease. Current evidence suggests both a mitochondrial function for parkin and a neuroprotective role, which may in fact be interrelated. The antiapoptotic effects of parkin have been widely reported, and may involve fundamental changes in the threshold for apoptotic cytochrome c release, but the substrate(s) involved in parkin dependent protection had not been identified. Here, we demonstrate the parkin-dependent ubiquitination of endogenous Bax comparing primary cultured neurons from WT and parkin KO mice and using multiple parkin-overexpressing cell culture systems. The direct ubiquitination of purified Bax was also observed in vitro following incubation with recombinant parkin. We found that parkin prevented basal and apoptotic stressinduced translocation of Bax to the mitochondria. Moreover, an engineered ubiquitination-resistant form of Bax retained its apoptotic function, but Bax KO cells complemented with lysine-mutant Bax did not manifest the antiapoptotic effects of parkin that were observed in cells expressing WT Bax. These data suggest that Bax is the primary substrate responsible for the antiapoptotic effects of parkin, and provide mechanistic insight into at least a subset of the mitochondrial effects of parkin.Parkinson's disease | apoptosis | neuroprotection | mitophagy P arkinson disease (PD) is a neurodegenerative disorder that affects 1-3% of the population over the age of 65 years (1). The symptoms include tremor, rigidity, bradykinesia, and postural instability. These physical characteristics are caused by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta and, to a lesser extent, the catecholaminergic neurons of the locus coeruleus. Although most cases of PD are sporadic in nature, a small number of genes are responsible for the rare familial forms of PD (2). Loss-of-function mutations within the PARK2 locus, which encodes the protein parkin, are the most common cause of autosomal recessive PD (3).Parkin is a 465-amino acid protein that is expressed in multiple tissues and functions as an E3 ubiquitin ligase (4). Ubiquitination of substrates is a tightly regulated process, requiring the combined activity of three enzymes: an E1 ubiquitin-activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin ligase (5). E3 ubiquitin ligases are responsible for substrate recognition, and as such contribute the specificity of a ubiquitin reaction. Defects in parkin-mediated ubiquitination may result in the failure to target specific substrates for degradation, leading to accumulation of potentially toxic proteins and consequent cell death (6). Parkin is widely neuroprotective (7); however, many of the putative parkin substrates reported to date are not thought to directly mediate toxicity in such a simple fashion [reviewed elsewhere (8...

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax

Johnson

Berger²,

Cortese³

et al. 2012

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

156

144

View full text Add to dashboard Cite

show abstract

“…Parkin plays a role in controlled proteolysis, modulation of the cellular anti-oxidants response and mitochondrial function and regulation of innate immunity (Alter et al 2011). It also has an anti-apoptotic effect (Berger et al 2009) and promotes autophagy. Thus, it may have a role in protection against intracellular pathogens by promoting bacterial killing while avoiding apoptosis (Deretic 2010).…”

Section: Interleukin (Il)-12/il-23/interferon (Ifn)γ Axis -mentioning

confidence: 99%

Insights from animal models on the immunogenetics of leprosy: a review

Adams

Peña

Sharma

et al. 2012

Mem. Inst. Oswaldo Cruz

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A variety of host immunogenetic factors appear to influence both an individual's susceptibility to infection with Mycobacterium leprae and the pathologic course of the disease. Animal models can contribute to a better understanding of the role of immunogenetics in leprosy through comparative studies helping to confirm the significance of various identified traits and in deciphering the underlying mechanisms that may be involved in expression of different disease related phenotypes. Genetically engineered mice, with specific immune or biochemical pathway defects, are particularly useful for investigating granuloma formation and resistance to infection and are shedding new light on borderline areas of the leprosy spectrum which are clinically unstable and have a tendency toward immunological complications. Though armadillos are less developed in this regard, these animals are the only other natural hosts of M. leprae and they present a unique opportunity for comparative study of genetic markers and mechanisms associable with disease susceptibility or resistance, especially the neurological aspects of leprosy. In this paper, we review the recent contributions of genetically engineered mice and armadillos toward our understanding of the immunogenetics of leprosy

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