Targeting mitochondrial metabolism for the treatment of acute myeloid leukemia (AML)

Abstract

Although most leukemic cells can be eradicated by chemotherapy, a subset acquires resistance to treatment through metabolic reprogramming. Recent studies have identified mitochondrial oxidative phosphorylation (OXPHOS) as being essential for energy maintenance and drug resistance in leukemic stem cells (LSCs), which highlights mitochondrial metabolism as a promising therapeutic target in acute myeloid leukemia (AML). Therapeutic strategies have focused on targeting the oxidative phosphorylation (OXPHOS), mitochondrial DNA, apoptosis, mitophagy, and the electron transport chain (ETC). The BCL-2 inhibitor venetoclax, approved in 2021, improves survival in combination with 5-azacitidine by promoting apoptosis and suppressing mitochondrial respiration. We are currently exploring novel therapeutic strategies that target mitochondrial metabolism, including: (1) development of novel kinase inhibitors that suppress mitochondrial metabolism, (2) inhibition of mitochondrial fission regulators (DNM1L and MFF) to downregulate OXPHOS, and (3) metabolic inhibition using mannose, a monosaccharide that competes with glucose metabolism. This review outlines recent advances in the understanding of mitochondrial metabolism in AML treatment resistance, highlights key molecular targets, and discusses future perspectives on innovative therapies based on these findings.