ER stress and mitochondrial dynamics: a tale of a wandering phosphatase DUSP28

Fission and fusion processes maintain the mitochondrial dynamics at a steady state and are altered during various cellular stresses. The mechanisms that regulate mitochondrial dynamics during ER stress are critically unknown. Here, we identified a dual specificity phosphatase DUSP28 with a novel role in regulating mitochondrial morphology during ER stress. Cytosolic DUSP28 translocates to mitochondria during ER stress via PERK activation and further promotes mitochondrial fission in a Drp1-dependent manner. Interestingly, the knockdown of DUSP28 activates PERK signaling and enhances ER expansion following mitochondrial elongation by enhancing S637 phosphorylation of Drp1. Overexpression of DUSP28-GFP could not rescue the loss of Drp1 function, indicating its necessity for mitochondrial fission. Further, the presence of DUSP28 on mitochondria prevents Parkin recruitment during CCCP-induced mitochondrial damage and follows STX17-dependent mitophagy. These findings illustrate the novel crosstalk between ER stress and DUSP28 phosphatase in maintaining the mitochondrial dynamics to sustain cellular stress.