The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1

Plun‐Favreau, Hélène; Klupsch, Kristina; Moisoi, Nicoleta; Gandhi, Sonia; Kjær, Susanne K.; Frith, David; Harvey, Kirsten; Deas, Emma; Harvey, Richard J.; McDonald, Neil Q.; Wood, Nicholas W.; Martins, L. Miguel; Downward, Julian

doi:10.1038/ncb1644

Cited by 442 publications

(426 citation statements)

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“…To investigate whether such a transcriptional response might be present in humans suffering from neurodegenerative disorders, we analyzed brains from PD patients as HtrA2 has been implicated in this disease. 5,6 Using qPCR, we compared the levels of CHOP and HERP mRNA expression in a group of control brains and a group of brains that fulfilled agreed criteria for the diagnosis of IPD. This revealed a relative increase in the ISR genes CHOP and HERP in a number of IPD patient brains compared with the control group (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

“…Part of the model has been suggested by the present study (gray hexagon). HtrA2 and the putative kinase PINK1 have been proposed to be components of a mitochondrial stress sensing pathway that might be defective in PD patients 6 Loss of HtrA2 induces a brain-specific stress response N Moisoi et al each sample. Samples were further incubated on ice for 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…5 More recently, HtrA2 and the putative kinase PINK1 have been proposed to be components of a mitochondrial stress sensing pathway that might be defective in PD patients. 6 HtrA2 may act to protect mitochondria from certain stresses, in a manner similar to the homologous stress-adaptive proteins DegP and DegS in bacteria, 7,8 and may be part of the mechanism underlying the well established but poorly understood link between mitochondrial dysfunction and neurodegenerative disease. 9 Eukaryotic cells respond to diverse stress signals with programmes of nuclear gene expression designed to repair cellular damage or induce apoptosis.…”

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Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

et al. 2008

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Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

et al. 2008

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“…PINK1 depletion reduces TRAP1 phosphorylation and oxidative stress resistance, suggesting that TRAP1 is a key signaling molecule mediating the PINK1-induced protection against oxidative stress. The same research group also reports mitochondrial protease high temperature requirement A2 (HtrA2/Omi) as a direct binding partner and indirect phosphorylation target of PINK1 (Plun-Favreau et al, 2007). However, Drosophila genetic studies do not indicate that HtrA2 acts in the same pathway as PINK1 (Yun et al, 2008).…”

Section: Other Mitochondrial Partners Of Pink1 In Mitochondrial Protementioning

confidence: 99%

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an agedependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.

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“…[8][9][10] This pro-survival activity is exerted through several mechanisms, including phosphorylation of the mitochondrial proteins TRAP1 and Omi/HtrA2, and regulation of mitochondrial calcium buffering. [11][12][13][14] Increasing data now indicate that PINK1 acts upstream of Parkin in an evolutionary conserved pathway implicated in regulating mitochondrial biogenesis, trafficking and fusion/ fission events, to maintain mitochondrial network health. 15 In particular, upon mitochondrial depolarization, PINK1 processing is impaired, determining a marked accumulation of the full-length protein on the surface of dysfunctional mitochondria, where it recruits Parkin.…”

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PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

et al. 2013

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Mutations in the PINK1 gene are a frequent cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase with neuroprotective activity, implicated in maintaining mitochondrial homeostasis and function. In concurrence with Parkin, PINK1 regulates mitochondrial trafficking and degradation of damaged mitochondria through mitophagy. Moreover, PINK1 can activate autophagy by interacting with the pro-autophagic protein Beclin-1. Here, we report that, upon mitochondrial depolarization, PINK1 interacts with and phosphorylates Bcl-xL, an anti-apoptotic protein also known to inhibit autophagy through its binding to Beclin-1. PINK1-Bcl-xL interaction does not interfere either with Beclin-1 release from Bcl-xL or the mitophagy pathway; rather it protects against cell death by hindering the pro-apoptotic cleavage of Bcl-xL. Our data provide a functional link between PINK1, Bcl-xL and apoptosis, suggesting a novel mechanism through which PINK1 regulates cell survival. This pathway could be relevant for the pathogenesis of PD as well as other diseases including cancer. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, with prevalence of 1% in the population older than 60 years. 1 Several biochemical abnormalities, including mitochondrial dysfunction, oxidative stress and misfolded protein damage, have been implicated in PD pathogenesis. 2 Although the majority of late-onset cases are sporadic, early-onset PD is frequently caused by mutations in genes with autosomal recessive inheritance, mainly Parkin (GeneID: 5071) and PINK1 (GeneID: 65018). 3 PINK1 encodes a 63 kDa mitochondrial protein kinase, which is processed by mitochondrial proteases to generate two smaller isoforms. [4][5][6][7] We and others have shown that PINK1 acts as a key neuroprotective protein, aimed at preventing mitochondrial dysfunction and apoptotic cell death in response to multiple stress conditions. [8][9][10] This pro-survival activity is exerted through several mechanisms, including phosphorylation of the mitochondrial proteins TRAP1 and Omi/HtrA2, and regulation of mitochondrial calcium buffering. [11][12][13][14] Increasing data now indicate that PINK1 acts upstream of Parkin in an evolutionary conserved pathway implicated in regulating mitochondrial biogenesis, trafficking and fusion/ fission events, to maintain mitochondrial network health. 15 In particular, upon mitochondrial depolarization, PINK1 processing is impaired, determining a marked accumulation of the full-length protein on the surface of dysfunctional mitochondria, where it recruits Parkin. This process results in the phosphorylation and/or ubiquitination of several mitochondrial substrates, leading to the selective quarantine of damaged mitochondria and their degradation through mitophagy. [16][17][18][19] In line with this, we reported that coexpression of mutant, but not wild-type (wt) PINK1, with mutant alpha-synuclein resulted in the formation of enlarged autophagosomes surrounding abnormal mitoch...

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The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1

Cited by 442 publications

References 42 publications

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage

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