Reduction in ETFDH expression optimizes cancer cell bioenergetics

Cancer cells reprogram their metabolism to meet the energy demands of neoplasia. We observed that the level of expression of mitochondrial enzyme electron transfer flavoprotein dehydrogenase (ETFDH) is unexpectedly decreased in most human malignancies relative to that in tissue-of-origin. Reduced ETFDH expression increases proliferation and neoplastic growth in vivo . This is a consequence of intracellular accumulation of amino acids leading to the activation of mTORC1, increase in B-cell lymphoma 6 ( BCL-6) levels, and BCL-6-dependent suppression of the eukaryotic translation initiation factor 4E-binding protein 1 ( EIF4EBP1 ) transcription. 4E-BP1 downregulation and mTORC1 hyperactivation increase mitochondrial biogenesis, function, and bioenergetic capacity thereby outweighing the advantage of flexibility in OXPHOS substrate utilization. Thus, the level of ETFDH expression plays a critical role in regulating trade-offs to optimize energy metabolism and coordinate it with signaling perturbations in cancer cells.