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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    • "This general stress response is often observed under pathologic conditions (Ong et al., 2013;Burté et al., 2015) and involves regulatory steps at both mitochondrial membranes. Mitochondrial depolarization triggers ubiquitin-dependent degradation of mitofusins as well as dephosphorylation and activation of DRP1 at the OMM (Cribbs and Strack, 2007;Cereghetti et al., 2008). At the same time, stress-induced proteolytic cleavage of OPA1 inhibits IMM fusion (Ishihara et al., 2006;Griparic et al., 2007;Song et al., 2007). "

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    • "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). Interestingly, miR-499 transgenic mice manifested a decline in hypertrophic parameters assessed by heart/body weight ratio, cardiac myocyte cross-sectional area, collagen content, heart chamber dimensions and cardiac function after ischaemia–reperfusion (I/R). "
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    • "We next asked if the elongated phenotype of SPG7 KD contributed to increased [Ca 2+ ] m retention. To test this, we measured [Ca 2+ ] m retention in wild-type cells overexpressing mitochondrial fission dominant-negative Drp1 K38A , known to result in elongated mitochondria (Cereghetti et al., 2008; Frank et al., 2001; Smirnova et al., 2001). As expected Drp1 K38A overexpression resulted in elongated mitochondria (Figures S2C–S2E). "
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