Novel Treatment of Acute Myeloid Leukemia by Targeting Complex II in the Mitochondrial Electron Transport Chain
Acute myeloid leukemia (AML) is a hematological malignancy characterized by an increased reliance on mitochondria-related energetic pathways (e.g., oxidative phosphorylation (OXPHOS)); and consistently, complex II (CII) of the mitochondrial electron transport chain has elevated activity in AML, providing a potential therapeutic target. Despite this, direct CII inhibition is unreported in AML research, and the mechanisms that lead to divergent fates of AML and normal cells upon CII inhibition are unknown. Thus, the primary aim is to characterize the effects of direct CII inhibition on AML cells through genetic and pharmacological approaches. AML cell lines were genetically impaired using lentiviral-mediated knockdown, suppressing CII activity and delaying in vitro and in vivo leukemia cell growth. To confirm these effects pharmacologically, an in silico screen and molecular docking study identified shikonin, a plant-derived bioactive, to bind to CII. Shikonin inhibits CII activity and is selectively cytotoxic to AML bulk and CD34+ cells but not normal progenitors. The metabolic consequences of CII impairment, monitored through stable isotope tracing, suppressed the oxidative tricarboxylic acid (TCA) cycle. Notably, CII inhibition results in activation of reductive carboxylation of glutamine, an alternate metabolic pathway that regenerates TCA intermediates when OXPHOS is impaired. Here, loss of CII activity results in divergent cell fates whereby normal hematopoietic, but not AML cells, sufficiently used reductive carboxylation of glutamine to overcome TCA cycle truncation, sustain aspartate levels, and avert cell death. Furthermore, chronic exposure to shikonin leads to metabolic reprogramming that is more glycolytic and less mitochondrial. This work provides insight into CII inhibition in AML, exposing reductive carboxylation to support aspartate biosynthesis as a novel metabolic vulnerability in AML targeted by shikonin, a newly identified CII inhibitor.