Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The stability and catalytic function of DUSP6 are maintained through conjugation of small ubiquitin-like modifier-1 (SUMO1) and SUMO2/3 at lysine-234 (K234), which is disrupted during oxidation through transcriptional up-regulation of SUMO-deconjugating enzyme, SENP1, causing DUSP6 degradation by ubiquitin-proteasome. deSUMOylation underlies DUSP6 degradation, Drp1-S616 hyperphosphorylation, mitochondrial fragmentation, and apoptosis induced by H₂O₂ in cultured cells or brain ischemia/reperfusion in mice. Overexpression of DUSP6, but not the SUMOylation-deficient DUSP6^K234R mutant, protected cells from apoptosis. Thus, DUSP6 exerts a cytoprotective role by directly dephosphorylating Drp1-S616, which is disrupted by deSUMOylation under oxidation.

线粒体裂变/融合失衡是凋亡细胞死亡的主要原因，通常是由两个丝氨酸S616和S637的Drp1磷酸化失调引起的。尽管已经描述了Drp1-S616磷酸化的激酶，但是其去磷酸化的磷酸酶仍然不清楚。在这里，我们显示双特异性磷酸酶6（DUSP6）使Drp1-S616去磷酸化，独立于其已知的底物ERK1 / 2。在正常条件下，DUSP6使Drp1-S616的磷酸化水平保持较低。DUSP6的稳定性和催化功能是通过在赖氨酸234（K234）上偶联小泛素样修饰物1（SUMO1）和SUMO2 / 3来保持的，在氧化过程中，SUMO去缀合酶的转录上调会破坏DUSP6的活性， SENP1，导致DUSP6被泛素-蛋白酶体降解。deSUMOylation是DUSP6降解的基础，培养细胞中的₂ O ₂或小鼠的脑缺血/再灌注。DUSP6的过表达，而不是^SUMOylation缺陷的DUSP6 ^K234R突变体，能保护细胞免于凋亡。因此，DUSP6通过直接使Drp1-S616脱磷酸而发挥细胞保护作用，Drp1-S616在氧化作用下被deSUMOylation破坏。