RT Journal Article
SR Electronic
T1 Mitochondrial Function is Preserved Under Cysteine Starvation via Glutathione Catabolism in NSCLC
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.10.06.511221
DO 10.1101/2022.10.06.511221
A1 Ward, Nathan P.
A1 Yoon, Sang Jun
A1 Flynn, Tyce
A1 Sherwood, Amanda
A1 Madej, Juliana
A1 DeNicola, Gina M.
YR 2022
UL http://biorxiv.org/content/early/2022/11/07/2022.10.06.511221.abstract
AB Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that mitochondrial glutathione sustains the function of the Fe-S proteins critical to oxidative metabolism. This is achieved through CHAC1 catabolism of the cysteine-containing tripeptide within the mitochondrial matrix. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a novel mechanism of mitochondrial resilience in response to nutrient stress.Competing Interest StatementThe authors have declared no competing interest.