Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin

• Published in: Cell death and differentiation Vol. 17; no. 11; pp. 1785 - 1794
• Main Authors: Cereghetti, G M, Costa, V, Scorrano, L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2010; Nature Publishing Group
• Subjects: 631/80/313/2377; 631/80/642/333; 631/80/82/23; Apoptosis; Apoptosis - drug effects; bcl-Associated Death Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Calcineurin - metabolism; Calcineurin Inhibitors; Cell Biology; Cell Cycle Analysis; Cell death; Colony-Forming Units Assay; Cyclophilin A - metabolism; Cytochrome; Cytochromes c - metabolism; Dynamins; Dyneins - metabolism; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - metabolism; HeLa Cells; Humans; Life Sciences; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Metabolism; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - metabolism; original-paper; Peptides - metabolism; Peptides - pharmacology; Permeability; Phosphatase; Phosphorylation; Physiology; Polypeptides; Protein Transport; Proteins; Staurosporine - pharmacology; Stem Cells; Tacrolimus Binding Proteins - metabolism; Tacrolimus Binding Proteins - pharmacology; Switzerland; calcineurin; mitochondria; fission; Drp1
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.61

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.