156 Oral - Models of Human Disease I - Diseases with a Neurological Focus
Saturday April 09, 9:00 AM - 9:15 AM

Authors:
Zhe Liao ¹; Kin Lam Wong ²; Esther Verheyen ¹

Affiliations:
1) Simon Fraser University, Canada; 2) Stanford University Stanford, USA

Keywords:
v. cell biology of disease; h. mitochondria

Cyclin-dependent kinase 8 is a serine/threonine kinase, which functions in regulating RNA polymerase II mediated transcription. Cdk8 forms a complex with Cyclin C, Mediator 12 (Med 12), and Mediator 13 (Med 13) that interacts with the core Mediator complex in a reversible fashion. While the regulatory role of Cdk8 in transcription is well-studied, we identified novel functions of Cdk8 in regulating mitochondrial morphology in Drosophila. When cdk8 is knocked down ubiquitously, we observe phenotypic effects including held-up and droopy wing postures, reduced life span, and defects in both flight and climbing abilities. Surprisingly, the observed phenotypic effects are characteristics of flies with either PTEN-induced putative kinase 1 (pink1) or parkin mutations, which are two well-known players associated with Parkinson’s disease (PD). Pink1 and Parkin normally function in regulating the homeostasis of mitochondria in a process known as mitophagy. Impaired or dysfunctional mitochondria will be recognized by Pink1 and Parkin and targeted for degradation by autophagy. Since tissue specific knock down of Cdk8 in either muscles or neurons also resulted in impaired climbing ability, we hypothesized that Cdk8 functions in a common pathway with Pink1 and Parkin in regulating mitochondria. Ectopic expression of Cdk8 in muscles significantly suppressed defects caused by the loss of function pink1 allele, pink1^B9, including rescue of the thorax indentation phenotype which is due to muscle degeneration, and rescued climbing activity relative to pink1^B9 mutants. In addition, mitochondrial and muscle fiber morphologies were restored when Cdk8 was overexpressed in the pink1^B9 mutant background. Finally, we examined the effect of Cdk8 on mitochondria under physiological conditions. Expression of Cdk8 is tightly associated with mitochondrial dynamics in a kinase-dependent fashion, as fission-like alterations were found after elevating Cdk8 expression and fusion-like morphology was induced after depleting cdk8 or expressing a kinase dead form of the protein. Together, we demonstrate that Cdk8 plays a novel function in regulating the homeostasis of mitochondria, and is able to revert the defective phenotypes caused by pink1^B9 mutant allele. Our findings suggest that modulation of Cdk8 may serve as a potential therapeutic target for patients with PD.