Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria

TLDR

Mitochondrial morphology is tightly controlled by the balance of fusion and fission, and excessive fragmentation arises when fusion is inhibited or the organelle is dysfunctional. Depolarization coupled with sustained cytosolic Ca²⁺ activates calcineurin, which dephosphorylates Drp1 at serine 637, enabling its translocation to mitochondria. This calcineurin‑dependent Drp1 translocation drives fragmentation of depolarized mitochondria, establishing a Ca²⁺–calcineurin–Drp1 loop that underlies dysfunction‑induced mitochondrial fragmentation.

Abstract

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.