BCKDK, a novel hypoxia-responsive kinase that exacerbates cerebral ischemia injury

Alterations of circulating amino acid profile have been observed in patients with ischemic stroke. However, whether ischemia disrupts amino acid metabolism in the brain tissue and subsequently potentiates cellular stress and cerebral injury have never been explored. Employing a metabolomics approach combined with metabolic flux analysis, impaired catabolism and significant enrichment of branched-chain amino acids (BCAAs) were identified in mouse primary neuron cells upon oxygen-glucose deprivation. Consistently, BCAA catabolism was also damaged in the brain of mouse with acute ischemic stroke, accompanied with suppressed activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) and upregulation of BCKDH kinase (BCKDK). Furthermore, restoration of BCAA catabolism by suppressing BCKDK via pharmacological inhibitor or silencing RNA dramatically alleviated cerebral ischemia injury in mice. Mechanistically, ischemia induces the expression of BCKDK via hypoxia-inducible factor 1alpha-mediated transcriptional activation and inhibits BCAA conversion into substrates for tricarboxylic acid cycle, contributing to potentiated energy deficiency, glutamate excitotoxicity, and neuronal injury. Collectively, this study identified BCKDK as a novel hypoxia-responsive factor and a promising therapeutic target for cerebral ischemia injury.