Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(2), P. 100048 - 100048

Published: Nov. 30, 2024

Copper (Cu) is an essential cofactor for metalloenzymes such as cytochrome c oxidase (CcO), the terminal enzyme of mitochondrial electron transport chain. Mutations that directly or indirectly prevent Cu to mitochondria result in lethal pediatric diseases, Menkes disease. There no clinically approved treatment We recently discovered investigational chemotherapy drug, elesclomol (ES), when complexed with (ES-Cu), rescues deficiency, activates CcO, and prevents perinatal lethality a mouse model However, ES-Cu also has potential trigger cuproptosis, type Cu-dependent cell death. Therefore, develop therapeutic agent disease, it critical determine index Cu-deficient models. To this end, we used rat cardiomyocyte line mottled-brindled severe disease toxicity efficacy ES-Cu. Our culture studies demonstrated EC50 ∼50-fold lower than IC50. Moreover, biomarkers toxicity, including lipoylated proteins subset iron-sulfur cluster-containing mitochondria, are activated only at ∼10-fold 25-fold higher its EC50. Importantly, none these mice treated doses study shows can deliver CcO both vitro vivo without triggering finding could facilitate use deficiency disorders, SIGNIFICANCE STATEMENT: Genetic copper causes which lacks treatment. Recently, Cu-transporting chemotherapeutic been reported. Because risk Cu-induced from ES-Cu, crucial index. Here, models were measured demonstrate restore cuproenzymes biomarkers.

Language: Английский

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Metal-Dependent Cell Death in Renal Fibrosis: Now and in the Future

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13279 - 13279

Published: Dec. 11, 2024

Renal fibrosis is a common final pathway underlying nearly almost all progressive kidney diseases. Metal ions are essential trace elements in organisms and involved important physiological activities. However, aberrations intracellular metal ion metabolism may disrupt homeostasis, causing cell death increasing susceptibility to various Accumulating evidence suggests complex association between metal-dependent renal fibrosis. In this article, we provide comprehensive overview of the specific molecular mechanisms their crosstalk, up-to-date supporting role fibrosis, therapeutic targeting strategies, research needs, aiming offer rationale for future clinical treatment

Language: Английский

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Mechanisms of Toxicant-Induced Acute Kidney Injury

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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