Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance

Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3′ UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs. [Display omitted] •RREB1 is required for AML development and leukemia stem cell maintenance•RREB1 deletion impairs mitochondrial activity and succinate metabolism•RREB1S cooperates with eEF1A1 to promote mitochondrial protein synthesis•Mitochondrial complex II inhibition overcomes venetoclax resistance in AML cells Han et al. find that RREB1 maintains leukemia stem cell (LSC) function by regulating mitochondrial function and identify a short RREB1 isoform, RREB1S, acting as a translational regulator to promote the nuclear-encoded mitochondrial protein synthesis by cooperating with eEF1A1. These findings lay the foundation for targeting LSC vulnerability.