Sepsis and shock states impose mitochondrial stress, and in response, adaptive mechanisms such as fission, fusion and mitophagy are induced to eliminate damaged portions of or entire dysfunctional mitochondria. The mechanisms underlying these events are being elucidated; yet a direct link between loss of mitochondrial membrane potential ΔΨm and the initiation of fission, fusion and mitophagy remains to be well characterized. The direct association between the magnitude of the ΔΨm and the capacity for mitochondria to buffer Ca²⁺ renders Ca²⁺ uniquely suited as the signal engaging these mechanisms in circumstances of mitochondrial stress that lower the ΔΨm. Herein, we show that the calcium/calmodulin-dependent protein kinase (CaMK) IV mediates an adaptive slowing in oxidative respiration that minimizes oxidative stress in the kidneys of mice subjected to either cecal ligation and puncture (CLP) sepsis or endotoxemia. CaMKIV shifts the balance towards mitochondrial fission and away from fusion by 1) directly phosphorylating an activating Serine616 on the fission protein DRP1 and 2) reducing the expression of the fusion proteins Mfn1/2 and OPA-1. CaMKIV, through its function as a direct PINK1 kinase and regulator of Parkin expression, also enables mitophagy. These data support that CaMKIV serves as a keystone linking mitochondrial stress with the adaptive mechanisms of mitochondrial fission, fusion and mitophagy that mitigate oxidative stress in the kidneys of mice responding to sepsis.

脓毒症和休克状态会施加线粒体压力，作为响应，诱导裂变、融合和线粒体自噬等适应性机制以消除受损部分或整个功能失调的线粒体。正在阐明这些事件背后的机制；然而，线粒体膜电位 ΔΨm 的丧失与裂变、融合和线粒体自噬的开始之间的直接联系仍有待充分表征。ΔΨm 的大小与线粒体缓冲 Ca ²⁺的能力之间的直接关联使得 Ca ²⁺在降低 ΔΨm 的线粒体压力情况下，特别适合作为参与这些机制的信号。在此，我们展示了钙/钙调蛋白依赖性蛋白激酶 (CaMK) IV 介导了氧化呼吸的适应性减慢，从而最大限度地减少了盲肠结扎和穿刺 (CLP) 败血症或内毒素血症小鼠肾脏中的氧化应激。CaMKIV 通过 1) 直接磷酸化裂变蛋白 DRP1 上的激活丝氨酸 616 和 2) 降低融合蛋白 Mfn1/2 和 OPA-1 的表达，将平衡转向线粒体裂变并远离融合。CaMKIV 通过其作为直接 PINK1 激酶和 Parkin 表达调节剂的功能，还可以实现线粒体自噬。