The impact of ER(UPR) on mitochondrial integrity mediated by PDK4.

ER and mitochondrial stress are often interconnected and considered major contributors to aging as well as neurodegeneration. Coordinated induction of ER(UPR) and mito(UPR) has been observed in diabetes and pulmonary disorders. However, in the context of aging and neurodegeneration, regulation of this intra-organellar crosstalk has remained relatively elusive. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial protein, accumulates at the ER-mitochondrial contact sites (MAMs) during ER stress. Classically, PDK4 is known to phosphorylate PDHA1 (pyruvate dehydrogenase E1 subunit alpha 1) and plays a significant role in regulating the oxidative phosphorylation-driven ATP production. In this study, we propose a non-canonical kinase-independent function of PDK4; we show that it acts as a connecting link between ER(UPR) and mito(UPR), with significance in aging and Alzheimer's disease (AD) associated neurodegeneration. Transcriptomics analyses show increased PDK4 levels upon drug-induced ER stress. We detect elevated PDK4 levels in lysates from human AD patient and mouse models as well as in ex vivo AD models. Additionally, exogenous expression of PDK4 was found to refine ER-mitochondria communication, significantly altering mitochondrial morphology and function. Further, we also observe defective autophagic clearance of mitochondria under such conditions. It is prudent to suggest that elevated PDK4 levels could be one of the key factors connecting ER(UPR) with mito(UPR), a phenotypic contributor in aging and in AD-like neurodegenerative disorders.