Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II

Abstract

We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.

Metabolic Dysregulation Contributes to the Progression of Alzheimer’s Disease

“…All these proteins can affect redox activity in mitochondria ( Yin et al, 2012 ). The redox state of mitochondria can regulate energy metabolism via the oxidization of several metabolic enzymes, including aconitase, α-ketoglutarate dehydrogenase (α-KGDH), malate dehydrogenase ( Reed et al, 2008 ), and succinyl-CoA-3-oxoacid CoA transferase (SCOT) ( Garcia et al, 2010 ), and complexes I ( Cortes-Rojo et al, 2020 ), II ( Jones et al, 2019 ), and V ( Kramer et al, 2018 ). It can also regulate S-glutathione glycosylation, a modification that reflects the redox state of mitochondria by reversibly forming mixed disulfide bonds between protein cysteine sulfhydryl and GSH ( Schafer and Buettner, 2001 ; Hill and Bhatnagar, 2012 ).…”

VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines

“…We focused on IRE1α and PERK, well-known participants in inducing apoptosis. Indeed, PERK has been shown to inhibit the translation initiation factor 2α (eukaryotic initiation factor 2 alpha (eIF2α) by phosphorylation, thereby, reducing protein synthesis and overload [ 23 , 24 , 25 ]. In accordance, our results revealed rapid phosphorylation of eIF2α in MV-4-11 cells within 15 min following VAS3947 exposure ( Figure 7 A).…”

“…AML cells have an abundant expression of proteins implicated in the GSH system [ 23 ] and are highly sensitive to drugs targeting GSH metabolism [ 23 ]. Interestingly, the use of an enzyme that degrades cysteine, a precursor for the synthesis of GSH, completely eradicates leukemic stem cells (LSCs) without any effect on normal hematopoietic stem/progenitor cells [ 24 ]. Indeed, the authors showed that the survival of ROS low LSCs is dependent on the availability of cysteine.…”

Mitochondrial determinants of response and resistance to venetoclaxpluscytarabine duplet therapy in acute myeloid leukemia

“…Furthermore, they displayed an enrichment in gene signatures related to leukemic stem cells, cysteine metabolism or mitochondria ( Supplementary Fig. S1H-S1J), all known markers of response to either VEN or VEN+AZA 25,[45][46][47] . Finally, transcriptomes of VEN-resistant AML patients are enriched in gene sets related to hypoxia and glycolysis.…”