Role of Cdk5 in Mitochondrial Dysfunction: Phosphorylation of KANSL1 and Impairment of PINK1-Mediated Mitophagy

Abstract Type 2 diabetes (T2D) is emerging as one of the most important risk factors for cognitive impairment and neurodegeneration, with mitochondrial dysfunction and defective mitophagy exacerbating disease progression. Despite the implication of aberrant cyclin-dependent kinase 5 (Cdk5) activation in T2D-neurodegeneration, the mechanisms linking Cdk5 hyperactivity to impaired mitochondrial quality control remain poorly defined. We therefore investigated whether Cdk5 regulates the epigenetic modulation of KAT8 Regulatory NSL Complex Subunit 1 (KANSL1), a newly discovered transcriptional regulator of PINK1-dependent mitophagy. Here in this study, we show that Cdk5 hyperactivation inhibits mitochondrial respiration, ATP generation, and mitophagy, leading to the accumulation of impaired mitochondria, while inhibition of Cdk5 by TFP5 rescues mitochondrial homeostasis in Cdk5-expressing neurons. The phosphoproteomic result revealed KANSL1 as a novel substrate of Cdk5, which specifically phosphorylates Ser268 of KANSL1. This study also demonstrates that Cdk5-mediated phosphorylation might decrease KANSL1 occupancy at the PINK1 promoter, attenuating its histone acetyltransferase activity to transcriptionally repress PINK1 expression, and may disrupt mitophagy. The upregulation of phospho-KANSL1 and downregulation of PINK1 were also validated in the brains of HFD-induced T2D mice. Our combined results reveal a previously unknown Cdk5–KANSL1–PINK1 signaling axis that connects the relationship of Cdk5 hyperactivation to mitochondrial quality control defects and positions KANSL1 phosphorylation as an alluring novel therapeutic target for neurodegeneration associated with diabetes.