Scutellarin Rescued Mitochondrial Damage through Ameliorating Mitochondrial Glucose Oxidation via the Pdk‐Pdc Axis

Abstract Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate‐keeping enzyme for mitochondrial glucose oxidation. In this study, a small‐molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and 13 C‐metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK‐PDC‐mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK‐N‐SH cells validated that SG could rescue mitochondrial damage via the PDK‐PDC axis, promote the MMP level and reduce the mitochondria‐dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK‐PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK‐PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.