Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo.
Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Xin
X
Qi
Marie-Helene
MH
Disatnik
Ning
N
Shen
Raymond A
RA
Sobel
Daria
D
Mochly-Rosen
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D016923:Cell Death; D034281:Dynamins / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D020303:Rats, Inbred Dahl; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured
D046912:Multiprotein Complexes; D009842:Oligopeptides; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D051745:Protein Kinase C-delta; C519851:Dnm1l protein, rat; D034281:Dynamins