Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis

Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5′-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate. [Display omitted] •Fumarate promotes monomer-to-dimer transition of ME2 to enhance mitobiogenesis•ME2 dimers activate DUT to foster thymidine generation and an increase of mtDNA•ME2 dimers relieve MRPL45 inhibition to enable mitochondrial protein production•ME2 methylation by PRMT1 inhibits dimerization and delays leukemia progression Wang et al. report that intramitochondrial ME2 connects mitobiogenesis to metabolism through fumarate. Fumarate promotes ME2 dimerization activating DUT and increasing mtDNA. Fumarate disrupts ME2-MRPL45 interaction, enhancing mitoribosome assembly and mitochondrial protein production. PRMT1 methylates ME2, inhibiting mitobiogenesis. Fumarate-ME2 axis is a regulatable link between nutrient substrate and mitochondrial generation.