The Mechanism Of Cell Metabolism Regulation In Necrosis

Programmed cell death is a kind of organized cell suicide regulated by intracellular signals,which is very important to cell population homeostasis,immune response and tumorigenesis inhibition.According to the different morphology,programmed cell death can be divided into apoptosis and necroptosis.In our study we found that aerobic respiration was activated in necrotic cells,but not in apoptotic cells.Inhibitors and loss-of-function experiments indicated that aerobic respiration contributed to necrosis,but not apoptosis.As a key regulator of necroptosis,RIP3 plays major roles in the activation of cell metabolism.In the process of necrosome(RIP1/RIP3/MLKL)formation,RIP3 phosphorylates and activates pyruvate dehydrogenase complex(PDC),which enhanced the use of pyruvate in the tricarboxylic acid cycle and increased aerobic respiration and ROS production.Necrosome,PDC and ROS worked as a positive feedback loop to induce downstream effect and necrosis.The molecular mechanism of PDC activation by RIP3 may provide a new perspective to design drugs for PDC disorder related diseases.