PYCR1 and central nervous system cancer: Indeed, it has recently been reported that IDH1 mutant glioma cells were more resistant to rotenone (ETC complex I inhibitor) due to enhanced activity of pyrroline 5-carboxylate reductase 1 (PYCR1), which can oxidize NADH and produce proline as a ‘metabolic bypass’ of ETC complex I [174] (Fig. 1), while breast and colon cancer IDH1 mutant cells have been reported to be more sensitive to ETC complex I inhibition by metformin [167].