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Updated: Jul 12, 2025

Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
Allosteric regulation of the lid domain of PCK2 as a novel strategy for modulating mitochondrial dynamics
Abstract:
Aberrant PCK2 overexpression has been linked to an unfavorable prognosis and shorter survival, particularly in hepatocellular carcinoma (HCC). Thus, the inactivation of PCK2 provides a promising strategy for HCC treatment. In this study, we used a chemical genetic strategy to identify a natural-derived small-molecule cucurbitacin B (CuB) as a selective PCK2 inhibitor. CuB covalently bound to PCK2 at a unique Cys63 site, blocking the Ω-loop lid domain formation via a previously undisclosed allosteric mechanism. Additionally, targeted lipidomics analysis also revealed that CuB destroyed mitochondrial membrane integrity, leading to the disruption of mitochondrial fusion-fission dynamics. Taken together, this study highlights the discovery of a small-molecule CuB, which reprograms lipid metabolism for controlling mitochondrial dynamics via targeting PCK2 in cancer cells.
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