Model depicting mechanism of necroptosis induction by mTOR and autophagy inhibition.

Renal carcinoma cells have activated mTOR, Nrf2 antioxidant defense and autophagy under basal conditions sufficient to manage ROS and survive. Autophagy inhibition with CQ blocks clearance of damaged mitochondrial through mitophagy. ROS is mitigated through the Nrf2 antioxidant defense pathway. mTOR inhibition promotes respiration and inhibits Nrf2 antioxidant defense. RIPKs are degraded by the ubiquitin proteasome system and damaged mitochondrial are cleared by mitophagy to maintain ROS homeostasis and cell survival. Pharmacological inhibition of both autophagy with CQ and mTOR with CCI-779 causes loss of antioxidant defense via Nrf2 and persistence of RIPKs and mitochondria leading to RIPK activation and ROS-mediated cell death by necroptosis.