Free Radicals in Cross Talk Between Autophagy and Apoptosis

Significance: Oxidative (reactive oxygen species ROS) and nitrosative (reactive nitrogen species RNS) stress affects many physiological processes, including survival and death. Although high levels of ROS/RNS mainly causes cell death, low levels of free radicals directly modulate the activities of transcriptional factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p53, and nuclear factor (erythroid-derived) 2-like (Nrf2), and regulate numerous protein kinase cascades that participate in the regulation of the cross talk between autophagy and apoptosis. Recent Advances: Low levels of ROS modify Atg4 and high mobility group box 1 (HMGB1) proteins, activate AMP-activated protein kinase (AMPK) and apoptosis signal-regulating kinase/c-Jun N-terminal kinase (JNK) pathways, or transactivate various proteins that could upregulate autophagy, leading to reductions in apoptosis. Transactivation of antioxidant genes blocks apoptosis and serves as a feedback loop to reduce autophagy. Free radicals could also activate protein kinase B (PKB, or Akt), preventing both autophagy and apoptosis. Stimulation of nitric oxide formation causes S-nitrosylation of several kinases, including JNK1 and IκB kinase β, which blocks autophagy and could promote apoptosis. However, S-nitrosylation of some proapoptotic proteins could block apoptosis. Critical Issues: Endoplasmic reticulum and mitochondria are the main sources of free radicals, which play an essential role in the regulation of apoptosis and autophagy. Oxidation of cardiolipin promotes cytochrome c release and apoptosis that potentially could be inhibited by autophagic clearance of damaged mitochondria. Elimination of damaged mitochondria reduces ROS accumulation, creating a feedback loop that causes inhibition of autophagy. Low levels of RNS could inhibit fission of mitochondria, which would block their degradation by autophagy and spare cells from apoptosis. Future Directions: Understanding of mechanisms that regulate the cross talk between cell fates is essential for discovery of therapeutic tools in the strenuous fight against various disorders, including neurodegeneration and cancer. Antioxid. Redox Signal. 21, 86–102.