Ojha et al. revealed a ROS-independent mechanism in glioblastoma (GBM) stem cells: Notch2 physically binds complex I’s Fe-S cluster subunits (NDUFV1/NDUFS2/NDUFS3) to promote RET, which maintains tumorigenicity primarily through NAD+/NADH reduction. The gene discussed is RET; the disease is glioblastoma.