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By Christina Towers, PhD.
Oxidative stress is a byproduct of an imbalance between oxidants and antioxidants present in the cell, resulting in dysfunctional redox signaling. This disproportion is caused by naturally occurring reactive oxygen species (ROS) and reactive nitrogen species (RNS) that can be derived from either extracellular sources or intracellularly as byproducts of essential cellular processes like metabolism. These species oxidize and remove electrons from the molecules they interact with, including many kinds of biomolecules, which can be detrimental to overall cellular function1. For example, ROS can induce single strand DNA breaks specifically in telomeric regions, resulting in collapsed replication forks, unreplicated single stranded DNA, and telomeric loss – a main contributor to cellular ageing2. ROS also affects many other pathologies, including cardiac dysfunction, cancer, and neurodegeneration. However, cells have employed several mechanisms to remove ROS/RNS to maintain redox signaling homeostasis. Antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidases (GPx) scavenge ROS/RNS and remove O2- and H2O2, preserving the healthy pool of reduced biomolecules. Interestingly, ROS/RNS are also critical signaling molecules and second messengers important for cell growth and proliferation; therefore, a balanced amount of ROS/RNS, also known as redoxstasis, is critical for overall cellular function.
Autophagy can play a crucial role in maintaining redoxstasis as oxidative stress and reactive oxygen/nitrogen species can induce autophagy, and studies have shown that anti-oxidant treatments can inhibit autophagy. Both O2- and H2O2 have been shown to affect autophagy downstream of nutrient starvation. There is likely a tight regulatory loop involving redox signaling, mitochondria, and mitophagy (the selective form of autophagy that degrades damaged mitochondria) as the mitochondria are thought to be the main sources of these autophagy-inducing ROS. Indeed, healthy mitochondria produce ROS as byproducts of oxidative phosphorylation; however, damaged mitochondria can generate copious amounts of ROS while simultaneously signaling their own self removal via mitophagy, forming a redox signal negative feedback loop. Acute oxidative stress can lead to rapid upregulation of autophagy via post-translational modifications of key autophagy regulators, including the protease ATG4b and the mitophagy specific protein Parkin. Sustained or chronic oxidative stress can also lead to transcriptional activation of chaperone-mediated autophagy via LAMP2A3.
Western Blot of Arsenic Trioxide on LC3B: LC3B Antibody [NB600-1384] - LC3B/MAP1 [NB600-1384] - Detection of LC3B in treated U87-MG (human glioblastoma astrocytoma) lysates. Arsenic trioxide has been used as an anticancer drug and is known to induce oxidative stress and DNA damage.
An elegant example highlighting the role of autophagy in maintaining redoxstasis is the p62-KEAP1-NRF2 signaling pathway. The canonical autophagy cargo protein and autophagy substrate p62 can directly interact with the E3 ubiquitin ligase KEAP1, outcompeting and sequestering it away from NRF2, a master regulator and transcription factor that binds to antioxidant response element (ARE-) containing genes4. KEAP1 is itself a redox responsive protein with several key cysteine residues, which, in their oxidized state, cause a conformational change, inhibiting KEAP1 from presenting NRF2 to the proteasome for degradation, therefore stabilizing NRF2 and activating antioxidant responsive genes. In the instance of autophagy inhibition, p62 levels are increased, sequestering KEAP1 and therefore activating NRF2 and its target genes. This mechanism exemplifies the critical role of crosstalk between autophagy and redox signaling in maintaining cellular homeostatsis.
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Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.
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