Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis
Year: 2025
Type: article
Abstract: Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.
Source: Cell Reports
Institutions: Peking University, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education, Huazhong Agricultural University, Hong Kong Baptist University, Southern University of Science and Technology, Shenzhen Bay Laboratory, Center for Life Sciences
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W4411929493