Extensive metabolomics, fluxomics & transcriptomics revealed that OPA1 inhibition rewires AML metabolism, rendering AML cells dependent on glutamine, sensitive to glutamine depletion/glutaminase inhibition, & prone to erastin-induced lipid peroxidation/ferroptosis.

Mechanistically, OPA1 inhibitors amplify apoptotic cristae remodeling upon stimulation and sensitize AML models to programmed cell death, independent of the mutational background.

Genetic targeting of OPA1 in combination with venetoclax significantly extends animal survival in AML xenograft models.

Using electron microscopy and morphometric analyses in AML cell lines and patient samples, we demonstrate that OPA1-dependent tightening of mitochondrial cristae is a common feature of therapy-resistant AML.