Elksnis 2021 Clin Sci (Lond)

From Bioblast
Publications in the MiPMap
Elksnis A, Schiffer TA, Palm F, Wang Y, Cen J, Turpaev K, Ngamjariyawat A, Younis S, Huang S, Shen Y, Leng Y, Bergsten P, Karlsborn T, Welsh N, Wang X (2021) Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK. Clin Sci (Lond) 135:2243-63.

Β» PMID: 34569605 Open Access

Elksnis Andris, Schiffer Tomas A, Palm Fredrik, Wang Yun, Cen Jing, Turpaev Kyril, Ngamjariyawat Anongnad, Younis Shady, Huang Suling, Shen Yu, Leng Ying, Bergsten Peter, Karlsborn Tony, Welsh Nils, Wang Xuan (2021) Clin Sci (Lond)

Abstract: The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies, but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of NOD mice with imatinib resulted in increased beta-cell AMPK phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against IAPP-aggregation, TXNIP upregulation and beta-cell death. AICAR mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme ECHS1. In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and ACC phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP downregulation, which in turn protects against beta-cell death. β€’ Keywords: AMPK, TXNIP, Cell death, Imatinib, Pancreatic beta cell, Respiratory chain β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: SE Uppsala Liss P, SE Stockholm Weitzberg E

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Kidney  Preparation: Isolated mitochondria 

Coupling state: OXPHOS, ET  Pathway: N, S  HRR: Oxygraph-2k 


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