Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria

Dulbecco-Telethon Institute, Padua, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2008; 105(41):15803-8. DOI: 10.1073/pnas.0808249105
Source: PubMed


Changes in mitochondrial morphology that occur during cell cycle, differentiation, and death are tightly regulated by the balance between fusion and fission processes. Excessive fragmentation can be caused by inhibition of the fusion machinery and is a common consequence of dysfunction of the organelle. Here, we show a role for calcineurin-dependent translocation of the profission dynamin related protein 1 (Drp1) to mitochondria in dysfunction-induced fragmentation. When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. Thus, fragmentation of depolarized mitochondria depends on a loop involving sustained Ca(2+) rise, activation of calcineurin, and dephosphorylation of Drp1 and its translocation to the organelle.

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    • "Chen et al. described small and fragmented mitochondria in both human and rat models of heart failure, which were associated with decreased OPA1 levels (Chen et al., 2009). Other studies in neonatal rat cardiac myocytes exposed to phenylephrine to induce hypertrophy (Fang et al., 2007), as well as, in vivo models of cardiac hypertrophy, also described decreases in Mfn2 mRNA levels (Fang et al., 2007) Calcineurin is an essential regulator of cardiac hypertrophy and heart failure (Heineke & Molkentin, 2006) and participates in the regulation of mitochondrial fission by DRP1 dephosphorylation (Cereghetti et al., 2008). Wang et al. showed that both the A and B-isoforms of the calcineurin catalytic subunit are direct targets of microRNA (miR)-499, increasing DRP1 phosphorylation at residue Ser 656 , thereby reducing mitochondrial fission (Wang et al., 2011). "
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    • "Calcineurin, which is a Ca 2+ -and calmodulin-dependent serine/threonine phosphatase that belongs to the protein phosphatase 2B family (Klee et al., 1979), is considered an important mediator of cellular signaling, and it is involved in processes, such as T-cell activation, cell death, and the dephosphorylation of target proteins, including transcription factors (de la Pompa et al., 1998; Liu et al., 1991; Yazdanbakhsh et al., 1995). The activation of calcineurin is involved in mitochondrial fission through the dephosphorylation of Drp1, which is the activated form of Drp1 (Cereghetti et al., 2008). "
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