Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.

Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.

Autophagy in cancer: Recent advances and future directions.

Autophagy is being explored as a potential therapeutic target for enhancing the cytotoxic effects of chemotherapeutic regimens in various malignancies. Autophagy plays a very important role in cancer pathogenesis. Here, we discuss the updates on the modulation of autophagy via dynamic interactions with different organelles and the exploitation of selective autophagy for exploring therapeutic strategies. We further discuss the role of autophagy inhibitors in cancer preclinical and clinical trials, novel autophagy inhibitors, and challenges likely to be faced by clinicians while inducting autophagy modulators in clinical practice.