Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. We show that Cdk8 promotes the phosphorylation of Drp1 at S616, a protein required for mitochondrial fission. Interestingly, Pink1, a mitochondrial kinase implicated in Parkinson’s disease, also phosphorylates Drp1 at the same residue. Indeed, overexpression of Cdk8 significantly suppresses the phenotypes observed in flies with low levels of Pink1, including elevated levels of ROS, mitochondrial dysmorphology, and behavioral defects. In summary, we propose that Pink1 and Cdk8 perform similar functions to promote Drp1-mediated fission.

果蝇中的Cdk8是脊椎动物CDK8和CDK19的直系同源物。这些蛋白质已被证明可以调节 RNA 聚合酶 II 的转录控制。我们发现Cdk8的神经元丢失严重缩短果蝇的寿命并导致爆炸敏感性。值得注意的是，这些缺陷可以通过在神经元细胞质中发现的人 CDK19 的表达来挽救，这表明 CDK19/Cdk8 具有非核功能。在这里，我们证明 Cdk8 在细胞质中起着至关重要的作用，它的缺失会导致肌肉和神经元中的线粒体伸长。我们发现内源性 GFP 标记的 Cdk8 可以在细胞质和细胞核中找到。我们发现 Cdk8 促进 Drp1 在 S616 处的磷酸化，Drp1 是线粒体裂变所需的蛋白质。有趣的是，Pink1（一种与帕金森病有关的线粒体激酶）也在相同残基处磷酸化 Drp1。事实上，Cdk8 的过度表达显着抑制了 Pink1 水平较低的果蝇中观察到的表型，包括 ROS 水平升高、线粒体畸形和行为缺陷。总之，我们认为 Pink1 和 Cdk8 执行类似的功能来促进 Drp1 介导的裂变。