BCKDK, A Novel Hypoxia-Responsive Kinase That Exacerbates Cerebral Ischemia Injury

 How long before your incompetent? doctor and hospital even know about this? I'm guessing never based on past behaviour!

Exacerbate is a verb that means to make a bad situation, problem, pain, or illness worse

BCKDK, A Novel Hypoxia-Responsive Kinase That Exacerbates Cerebral Ischemia Injury

Boya Liao, PhD, MSocSc(Psy) https://orcid.org/0000-0001-7659-8406, Fang Zhang, MD https://orcid.org/0000-0002-4634-2749, 

Chang Han, MPhil https://orcid.org/0000-0002-6282-1256, Xinyao Yi, MSc, 

Ziyi Zhang, MPhil, Leigang Jin, PhD https://orcid.org/0000-0002-6916-4009,

Fei Meng, MSc https://orcid.org/0000-0002-8750-7896, Stanley Sau-Ching Wong, MD https://orcid.org/0000-0002-8763-5687, 

Ruby L.C. Hoo, PhD https://orcid.org/0000-0001-9633-7078 rubyhoo@hku.hk, Leiluo Geng, PhD https://orcid.org/0000-0003-2886-3476 llgeng@hku.hk, and Wei Jia, PhD https://orcid.org/0000-0002-3739-8994 weijia2@hku.hkAuthor Info & Affiliations

Stroke

New online

https://doi.org/10.1161/STROKEAHA.125.053856

Abstract

BACKGROUND:

Alterations in circulating amino acid profiles have been observed in ischemic stroke patients; however, whether cerebral ischemia disrupts amino acid metabolism within brain tissue and whether this disruption contributes to cellular stress and cerebral injury remain unknown. This hypothesis-testing study investigates disrupted BCAA (branched-chain amino acid) catabolism as a key mechanism of ischemic brain damage and evaluates BCKDK (branched-chain α-keto acid dehydrogenase kinase) as a novel therapeutic target.

METHODS:

Mouse primary cortical neurons subjected to oxygen-glucose deprivation and brain tissue from a mouse acute ischemic stroke model were used as experimental systems. Untargeted metabolomics and metabolic flux analysis were used to characterize BCAA metabolism in both models. In vivo pharmacological inhibition or in vitro knockdown of BCKDK was performed using BT2 treatment or RNA interference. Primary outcome variables included infarct volume, BCKDH (branched-chain α-keto acid dehydrogenase) enzyme activity, neuronal viability, and markers of energy metabolism and glutamate excitotoxicity. Between-group differences were evaluated using 1-way ANOVA; data are presented as mean ± SD with 95% CIs and corresponding P values.

RESULTS:

Metabolomics analysis of oxygen-glucose deprivation-exposed primary neurons revealed impaired BCAA catabolism and significant BCAA accumulation compared with normoxic controls. In ischemic mouse brain tissue, BCKDH activity was significantly suppressed, and BCKDK expression was markedly upregulated relative to sham-operated animals. Both pharmacological and genetic suppression of BCKDK substantially reduced cerebral ischemic injury, as evidenced by decreased infarct volume and improved neuronal survival (95% CI and P values per comparison). Mechanistically, ischemia-induced BCKDK expression via HIF-1α (hypoxia-inducible factor 1α)-mediated transcriptional activation, which inhibited BCAA conversion to tricarboxylic acid cycle substrates, thereby potentiating energy deficiency and glutamate excitotoxicity.

CONCLUSIONS:

These data identify BCKDK as a novel hypoxia-responsive factor whose upregulation drives disrupted BCAA catabolism as a key mechanism of ischemic neuronal injury. BCKDK represents a promising therapeutic target for cerebral ischemia, directly supported by both in vitro and in vivo experimental evidence presented here.(Which doesn't correspond to exacerbates in the title! So which is it? Your mentors and senior researchers are so incompetent they didn't catch that?)

Graphical Abstract

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