Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin.
During apoptosis, mitochondria lose their membrane potential and undergo fragmentation around the time of release of cytochrome c. Apoptotic fission is at least in part sustained by the translocation of dynamin-related protein 1 (Drp1), normally located in the cytosol, to mitochondria. This process depends on dephosphorylation of Drp1 by the phosphatase calcineurin. Here, we report the identification of a novel inhibitor of this process. A polypeptide (PPD1) from the immunophilin FKBP52 inhibits calcineurin activation triggered by mitochondrial dysfunction. PPD1 blocks Drp1 translocation to mitochondria and fragmentation of the organelle. PPD1 delays apoptosis by intrinsic stimuli by preventing fragmentation and release of cytochrome c. Cells expressing PPD1 display enhanced clonogenic ability after exposure to staurosporine. A genetic analysis revealed that the activity of PPD1 is independent of the BH3-only protein BAD, another target of calcineurin during apoptosis, and is not additive to inhibition of Drp1. Thus, PPD1 is a novel inhibitor of apoptosis that elucidates the function of calcineurin-dependent mitochondrial fragmentation in the amplification of cell death.
Cereghetti
G M
GM
Department of Cellular Physiology and Metabolism, University of Geneva, Switzerland.
Costa
V
V
Scorrano
L
L
D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D003114:Colony-Forming Units Assay; D021984:Cyclophilin A / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins; D004398:Dyneins / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D021381:Protein Transport; D019311:Staurosporine / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D065095:Calcineurin Inhibitors; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D051025:bcl-Associated Death Protein; D045304:Cytochromes c; D019703:Calcineurin; D020558:GTP Phosphohydrolases; D004398:Dyneins; C110768:DNM1L protein, human; D034281:Dynamins; D021984:Cyclophilin A; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D019311:Staurosporine