Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release.

Autosomal-recessive mutations in the Parkin gene are the second most common cause of familial Parkinson's disease (PD). Parkin deficiency leads to the premature demise of the catecholaminergic neurons of the ventral midbrain in familial PD. Thus, a better understanding of parkin function may elucidate molecular aspects of their selective vulnerability in idiopathic PD. Numerous lines of evidence suggest a mitochondrial function for parkin and a protective effect of ectopic parkin expression. Since mitochondria play a critical role in cell survival/cell death through regulated cytochrome c release and control of apoptosis, we sought direct evidence of parkin function in this pathway. Mitochondria were isolated from cells expressing either excess levels of human parkin or shRNA directed against endogenous parkin and then treated with peptides corresponding to the active Bcl-2 homology 3 (BH3) domains of pro-apoptotic proteins and the threshold for cytochrome c release was analyzed. Data obtained from both rodent and human neuroblastoma cell lines showed that the expression levels of parkin were inversely correlated with cytochrome c release. Parkin was found associated with isolated mitochondria, but its binding per se was not sufficient to inhibit cytochrome c release. In addition, pathogenic parkin mutants failed to influence cytochrome c release. Furthermore, PINK1 expression had no effect on cytochrome c release, suggesting a divergent function for this autosomal recessive PD-linked gene. In summary, these data demonstrate a specific autonomous effect of parkin on mitochondrial mechanisms governing cytochrome c release and apoptosis, which may be relevant to the selective vulnerability of certain neuronal populations in PD.

[1]  Jian Feng,et al.  Parkin Protects Dopaminergic Neurons against Microtubule-depolymerizing Toxins by Attenuating Microtubule-associated Protein Kinase Activation* , 2009, Journal of Biological Chemistry.

[2]  YongSung Kim,et al.  PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. , 2008, Biochemical and biophysical research communications.

[3]  J. Fitzgerald,et al.  Emerging pathways in genetic Parkinson’s disease: Autosomal‐recessive genes in Parkinson’s disease – a common pathway? , 2008, The FEBS journal.

[4]  R. Youle,et al.  Parkin is recruited selectively to impaired mitochondria and promotes their autophagy , 2008, The Journal of cell biology.

[5]  K. Abe,et al.  Ubiquitin-Mediated Stress Response in the Spinal Cord After Transient Ischemia , 2008, Stroke.

[6]  D. Selkoe,et al.  Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1. , 2008, Human molecular genetics.

[7]  M. LaVoie,et al.  The effects of oxidative stress on parkin and other E3 ligases , 2007, Journal of neurochemistry.

[8]  Ruifeng Lu,et al.  Drosophila Overexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities , 2007, The Journal of Neuroscience.

[9]  C. Culmsee,et al.  Parkin Mediates Neuroprotection through Activation of IκB Kinase/Nuclear Factor-κB Signaling , 2007, The Journal of Neuroscience.

[10]  G. Schellenberg,et al.  Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients , 2007, Annals of neurology.

[11]  D. Latchman,et al.  Induction of parkin expression in the presence of oxidative stress , 2006, The European journal of neuroscience.

[12]  Sunhong Kim,et al.  Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin , 2006, Nature.

[13]  Changan Jiang,et al.  Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin , 2006, Nature.

[14]  R. Swerdlow,et al.  Mitochondrial dysfunction and caspase activation in rat cortical neurons treated with cocaine or amphetamine , 2006, Brain Research.

[15]  S. Armstrong,et al.  Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. , 2006, Cancer cell.

[16]  T. Mitsui,et al.  Parkin enhances mitochondrial biogenesis in proliferating cells. , 2006, Human molecular genetics.

[17]  Olga Pletnikova,et al.  Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. , 2005, Human molecular genetics.

[18]  D. Selkoe,et al.  Dopamine covalently modifies and functionally inactivates parkin , 2005, Nature Medicine.

[19]  R. Takahashi,et al.  Parkin Phosphorylation and Modulation of Its E3 Ubiquitin Ligase Activity* , 2005, Journal of Biological Chemistry.

[20]  D. Green,et al.  The Pathophysiology of Mitochondrial Cell Death , 2004, Science.

[21]  G. Mardon,et al.  Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress , 2004, Development.

[22]  A. Mailloux,et al.  Cyclosporin A but not estradiol can protect endothelial cells against etoposide-induced apoptosis. , 2004, Endothelium : journal of endothelial cell research.

[23]  F. Lopera,et al.  Autosomal Recessive Juvenile Parkinsonism Cys212tyr Mutation in Parkin Renders Lymphocytes Susceptible to Dopamine-and Iron-mediated Apoptosis Patients and Methods , 2022 .

[24]  K. Winklhofer,et al.  Inactivation of Parkin by Oxidative Stress and C-terminal Truncations , 2003, Journal of Biological Chemistry.

[25]  T. Dawson,et al.  Molecular Pathways of Neurodegeneration in Parkinson's Disease , 2003, Science.

[26]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[27]  J. Haines,et al.  Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease , 2003, Annals of neurology.

[28]  L. Pallanck,et al.  Parkin A Multipurpose Neuroprotective Agent? , 2003, Neuron.

[29]  J. C. Greene,et al.  Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  E. Hirsch,et al.  Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. , 2003, Human molecular genetics.

[31]  T. Dawson,et al.  Rare genetic mutations shed light on the pathogenesis of Parkinson disease. , 2003, The Journal of clinical investigation.

[32]  S. Korsmeyer,et al.  Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. , 2002, Cancer cell.

[33]  G. Fiskum,et al.  BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability. , 2001, The Journal of biological chemistry.

[34]  K. Vousden,et al.  PUMA, a novel proapoptotic gene, is induced by p53. , 2001, Molecular cell.

[35]  J. Martinou,et al.  Mitochondria as the central control point of apoptosis. , 2000, Trends in cell biology.

[36]  J. Martinou,et al.  Bid Induces the Oligomerization and Insertion of Bax into the Outer Mitochondrial Membrane , 2000, Molecular and Cellular Biology.

[37]  J. Martinou,et al.  Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. , 2000, The Biochemical journal.

[38]  Luca Scorrano,et al.  Mitochondria and cell death. Mechanistic aspects and methodological issues. , 1999, European journal of biochemistry.

[39]  S. Korsmeyer,et al.  Caspase Cleaved BID Targets Mitochondria and Is Required for Cytochrome c Release, while BCL-XL Prevents This Release but Not Tumor Necrosis Factor-R1/Fas Death* , 1999, The Journal of Biological Chemistry.

[40]  Y. Agid,et al.  Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism , 1998, The Lancet.

[41]  M. Polymeropoulos,et al.  Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson’s disease , 1998, Human Genetics.

[42]  Xiaodong Wang,et al.  Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors , 1998, Cell.

[43]  J C Reed,et al.  Bax directly induces release of cytochrome c from isolated mitochondria. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[45]  D. Turnbull,et al.  A microtiter plate assay for cytochrome c oxidase in permeabilized whole cells. , 1993, Analytical biochemistry.

[46]  E. Stefani,et al.  A novel N18TG2 x mesencephalon cell hybrid expresses properties that suggest a dopaminergic cell line of substantia nigra origin , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[47]  V. Ritov,et al.  Alamethicin-induced pore formation in biological membranes. , 1992, General physiology and biophysics.

[48]  D. Benson,et al.  Alzheimer's disease and Parkinson's disease , 1988, Neurology.

[49]  C. Culmsee,et al.  Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  L. Scorrano,et al.  Mitochondria and cell death. Mechanistic aspects and methodological issues. , 1999, European journal of biochemistry.