scispace - formally typeset

Journal ArticleDOI

Parkin promotes cell survival via linear ubiquitination.

17 Apr 2013-The EMBO Journal (John Wiley & Sons, Ltd)-Vol. 32, Iss: 8, pp 1072-1074

TL;DR: Muller‐Rischart et al (2013) uncover an autophagy‐independent pathway involving Parkin‐mediated activation of the LUBAC ubiquitin ligase to prevent mitochondrial impairment and thereby to promote survival.

AbstractMitochondrial dysfunction has been linked to the pathogenesis of Parkinson's disease (PD). PD‐associated mutants of Parkin show defects in mitophagy, suggesting that Parkin exerts its neuroprotective role by removal of damaged mitochondria. Muller‐Rischart et al (2013) now uncover an autophagy‐independent pathway involving Parkin‐mediated activation of the LUBAC ubiquitin ligase to prevent mitochondrial impairment and thereby to promote survival. PD represents the most common movement disorder and is caused by dopaminergic neurodegeneration. As the majority of cases arise sporadically, the identification of monogenetic variants marked the beginning of a new era in PD research. Loss‐of‐function mutations mapped to the Parkin ubiquitin ligase and PINK1 kinase loci were shown to cause autosomal recessive juvenile parkinsonism (Kitada et al , 1998). The generation of PINK1 and Parkin deletion mutants in Drosophila illustrated their requirement for the maintenance of mitochondrial integrity (Clark et al , 2006) and supported the notion that mitochondrial dysfunction is a major etiological factor in PD. These reports also demonstrated the genetic epistasis of PINK1 and Parkin, placing them in a common or converging pathway. Further studies revealed their involvement in the autophagic removal of damaged mitochondria (Narendra et al , 2008). PINK1 is selectively retained and stabilized at the outer membrane of depolarized mitochondria and serves as a signal for Parkin recruitment and activation. Subsequent ubiquitination of mitochondrial proteins by Parkin drives affected mitochondria into autophagosomes (Geisler et al , 2010). In addition, mounting evidence …

Topics: Parkin (72%), PINK1 (62%), Mitophagy (59%), Ubiquitin ligase (53%), Mitochondrion (51%)

...read more

Content maybe subject to copyright    Report

Citations
More filters

Journal ArticleDOI
TL;DR: The hypotheses that impairment of mitochondrial quality control via suppression of PINK1 function should produce failures of turnover, accumulation of senescent mitochondria in the axon, defects in mitochondrial traffic, and a significant shift in the mitochondrial fission–fusion steady state are tested.
Abstract: Maintenance of healthy mitochondria is crucial in cells, such as neurons, with high metabolic demands, and dysfunctional mitochondria are thought to be selectively degraded. Studies of chemically uncoupled cells have implicated PINK1 mitochondrial kinase, and Parkin E3 ubiquitin ligase in targeting depolarized mitochondria for degradation. However, the role of the PINK1/Parkin pathway in mitochondrial turnover is unclear in the nervous system under normal physiological conditions, and we understand little about the changes that occur in the mitochondrial life cycle when turnover is disrupted. Here, we evaluated the nature, location, and regulation of quality control in vivo using quantitative measurements of mitochondria in Drosophila nervous system, with deletion and overexpression of genes in the PINK1/Parkin pathway. We tested the hypotheses that impairment of mitochondrial quality control via suppression of PINK1 function should produce failures of turnover, accumulation of senescent mitochondria in the axon, defects in mitochondrial traffic, and a significant shift in the mitochondrial fission–fusion steady state. Although mitochondrial membrane potential was diminished by PINK1 deletion, we did not observe the predicted increases in mitochondrial density or length in axons. Loss of PINK1 also produced specific, directionally balanced defects in mitochondrial transport, without altering the balance between stationary and moving mitochondria. Somatic mitochondrial morphology was also compromised. These results strongly circumscribe the possible mechanisms of PINK1 action in the mitochondrial life cycle and also raise the possibility that mitochondrial turnover events that occur in cultured embryonic axons might be restricted to the cell body in vivo, in the intact nervous system.

57 citations


Journal ArticleDOI
TL;DR: It is established that Parkin functions to eliminate LEC mitochondria depolarized/damaged upon oxidative stress exposure and that elimination of damaged mitochondria by Parkin is important for LEC homeostasis and survival.
Abstract: Age-related cataract is associated with oxidative stress and death of lens epithelial cells (LECs) whose survival is dependent on functional mitochondrial populations. Oxidative stress-induced depolarization/damage of LEC mitochondria results in increased reactive oxygen species (ROS) levels and cell death suggesting the need for a LEC mechanism to remove mitochondria depolarized/damaged upon oxidative stress exposure to prevent ROS release and LEC death. To date, a mechanism(s) for removal of depolarized/damaged LEC mitochondria has yet to be identified and the importance of eliminating oxidative stress-damaged mitochondria to prevent LEC ROS release and death has not been established. Here, we demonstrate that Parkin levels increase in LECs exposed to H2O2-oxidative stress. We establish that Parkin translocates to LEC mitochondria depolarized upon oxidative stress exposure and that Parkin recruits p62/SQSTM1 to depolarized LEC mitochondria. We demonstrate that translocation of Parkin results in the elimination of depolarized/damaged mitochondria and that Parkin clearance of LEC mitochondria is dependent on its ubiquitin ligase activity. Importantly, we demonstrate that Parkin elimination of damaged LEC mitochondria results in reduced ROS levels and increased survival upon oxidative stress exposure. These results establish that Parkin functions to eliminate LEC mitochondria depolarized/damaged upon oxidative stress exposure and that elimination of damaged mitochondria by Parkin is important for LEC homeostasis and survival. The data also suggest that mitochondrial quality control by Parkin could play a role in lens transparency.

21 citations


Journal ArticleDOI
TL;DR: Under conditions of chronic MI, mitochondrial dysfunction and disruption of autophagosomal clearance are associated with Parkin expression.
Abstract: BACKGROUND To study the role of Parkin in the regulation of mitochondrial autophagy in the heart by assessing mitochondrial autophagy and changes in Parkin protein expression in rat myocardium after myocardial infarction (MI). MATERIAL AND METHODS Rats were randomly assigned to three groups: control, sham, and MI. Four weeks after induction of MI, ultrasonic examination of the rats was performed to measure left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), left ventricular ejection fraction (EF), left ventricular fractional shortening (FS), and left ventricular diastolic/systolic volume. Rat myocardium was collected from each group and examined for changes in morphology, size, and amount of mitochondria and autophagosomes by transmission electronic microscopy. A Western blot was performed to analyze the levels of Parkin and the autophagy-related protein LC3. RESULTS Four weeks after MI, cardiac function of the MI rats was impaired compared with the control rats. Both LVESD and LVEDD were elevated in the MI rats (p 0.05). In addition, the levels of the autophagy-related proteins LC3II/LC3I were elevated in the myocardium after MI (p<0.05) and the activity of Parkin was significantly reduced (p<0.05). CONCLUSIONS Under conditions of chronic MI, mitochondrial dysfunction and disruption of autophagosomal clearance are associated with Parkin expression.

13 citations


Cites background from "Parkin promotes cell survival via l..."

  • ...Moreover, Parkin could mediate selective clearance of mitochondria by autophagy in cells treated with mitochondrial uncoupler for 24 hours [15,16]....

    [...]


Journal ArticleDOI
09 Jun 2019
TL;DR: Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.
Abstract: PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson's disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing.We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions.In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions.The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.

12 citations


Cites background from "Parkin promotes cell survival via l..."

  • ...A key role of PRKN in mitochondrial macroautophagy (mitophagy) has been reported in different models of the disease [10-14]....

    [...]


Journal ArticleDOI
TL;DR: The findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin.
Abstract: Mutations in the parkin gene (PRKN) are the most common cause of autosomal-recessive juvenile Parkinson's disease (PD). PRKN encodes an E3 ubiquitin ligase that is involved in multiple regulatory functions including proteasomal-mediated protein turnover, mitochondrial function, mitophagy, and cell survival. However, the precise molecular events mediated by PRKN mutations in PRKN-associated PD (PRKN-PD) remain unknown. To elucidate the cellular impact of parkin mutations, we performed an RNA sequencing study in skin fibroblasts from PRKN-PD patients carrying different PRKN mutations (n = 4) and genetically unrelated healthy subjects (n = 4). We identified 343 differentially expressed genes in PRKN-PD fibroblasts. Gene ontology and canonical pathway analysis revealed enrichment of differentially expressed genes in processes such as cell adhesion, cell growth, and amino acid and folate metabolism among others. Our findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin.

11 citations


References
More filters

Journal ArticleDOI
09 Apr 1998-Nature
TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
Abstract: Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

4,613 citations


"Parkin promotes cell survival via l..." refers background in this paper

  • ...Loss-of-function mutations mapped to the Parkin ubiquitin ligase and PINK1 kinase loci were shown to cause autosomal recessive juvenile parkinsonism (Kitada et al, 1998)....

    [...]


Journal ArticleDOI
TL;DR: It is shown that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells and this recruitment promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondira in the pathogenesis of Parkinson's disease.
Abstract: Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

3,009 citations


"Parkin promotes cell survival via l..." refers background in this paper

  • ...Further studies revealed their involvement in the autophagic removal of damaged mitochondria (Narendra et al, 2008)....

    [...]


Journal ArticleDOI
TL;DR: Functional links between PINK1, Parkin and the selective autophagy of mitochondria, which is implicated in the pathogenesis of Parkinson's disease, are provided.
Abstract: Parkinson's disease is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive Parkinson's disease. However, their molecular contribution to pathogenesis remains unclear. Here, we reveal important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage, ubiquitylation and autophagy in non-neuronal and neuronal cells. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, we identified VDAC1 (voltage-dependent anion channel 1) as a target for Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Moreover, pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final clearance through mitophagy. Thus, our data provide functional links between PINK1, Parkin and the selective autophagy of mitochondria, which is implicated in the pathogenesis of Parkinson's disease.

2,099 citations


"Parkin promotes cell survival via l..." refers background in this paper

  • ...Subsequent ubiquitination of mitochondrial proteins by Parkin drives affected mitochondria into autophagosomes (Geisler et al, 2010)....

    [...]


Journal ArticleDOI
28 Jun 2006-Nature
TL;DR: Removal of Drosophila PINK1 homologue function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress, which underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.
Abstract: Parkinson's disease is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction has been implicated as an important trigger for Parkinson's disease-like pathogenesis because exposure to environmental mitochondrial toxins leads to Parkinson's disease-like pathology. Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1 ; PARK6 ) and parkin (PARK2 ), which are also associated with sporadic forms of Parkinson's disease. PINK1 encodes a putative serine/threonine kinase with a mitochondrial targeting sequence. So far, no in vivo studies have been reported for pink1 in any model system. Here we show that removal of Drosophila PINK1 homologue (CG4523; hereafter called pink1) function results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress. Pink1 localizes to mitochondria, and mitochondrial cristae are fragmented in pink1 mutants. Expression of human PINK1 in the Drosophila testes restores male fertility and normal mitochondrial morphology in a portion of pink1 mutants, demonstrating functional conservation between human and Drosophila Pink1. Loss of Drosophila parkin shows phenotypes similar to loss of pink1 function. Notably, overexpression of parkin rescues the male sterility and mitochondrial morphology defects of pink1 mutants, whereas double mutants removing both pink1 and parkin function show muscle phenotypes identical to those observed in either mutant alone. These observations suggest that pink1 and parkin function, at least in part, in the same pathway, with pink1 functioning upstream of parkin. The role of the pink1–parkin pathway in regulating mitochondrial function underscores the importance of mitochondrial dysfunction as a central mechanism of Parkinson's disease pathogenesis.

1,551 citations


"Parkin promotes cell survival via l..." refers background in this paper

  • ...The generation of PINK1 and Parkin deletion mutants in Drosophila illustrated their requirement for the maintenance of mitochondrial integrity (Clark et al, 2006) and supported the notion that mitochondrial dysfunction is a major etiological factor in PD....

    [...]


Journal ArticleDOI
14 Jul 2006-Cell
TL;DR: Evidence is provided that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion.
Abstract: Mitochondria amplify activation of caspases during apoptosis by releasing cytochrome c and other cofactors. This is accompanied by fragmentation of the organelle and remodeling of the cristae. Here we provide evidence that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion. OPA1 does not interfere with activation of the mitochondrial "gatekeepers" BAX and BAK, but it controls the shape of mitochondrial cristae, keeping their junctions tight during apoptosis. Tightness of cristae junctions correlates with oligomerization of two forms of OPA1, a soluble, intermembrane space and an integral inner membrane one. The proapoptotic BCL-2 family member BID, which widens cristae junctions, also disrupts OPA1 oligomers. Thus, OPA1 has genetically and molecularly distinct functions in mitochondrial fusion and in cristae remodeling during apoptosis.

1,287 citations


Related Papers (5)