Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

Abstract

Many cellular redox reactions housed within mitochondria, peroxisomes and the endoplasmic reticulum (ER) generate hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). The contribution of each organelle to the total cellular ROS production is considerable, but varies between cell types and also over time. Redox-regulatory enzymes are thought to assemble at a “redox triangle” formed by mitochondria, peroxisomes and the ER, assembling “redoxosomes” that sense ROS accumulations and redox imbalances. The redoxosome enzymes use ROS, potentially toxic by-products made by some redoxosome members themselves, to transmit inter-compartmental signals via chemical modifications of downstream proteins and lipids. Interestingly, important components of the redoxosome are ER chaperones and oxidoreductases, identifying ER oxidative protein folding as a key ROS producer and controller of the tri-organellar membrane contact sites (MCS) formed at the redox triangle. At these MCS, ROS accumulations could directly facilitate inter-organellar signal transmission, using ROS transporters. In addition, ROS influence the flux of Ca2+ ions, since many Ca2+ handling proteins, including inositol 1,4,5 trisphosphate receptors (IP3Rs), SERCA pumps or regulators of the mitochondrial Ca2+ uniporter (MCU) are redox-sensitive. Fine-tuning of these redox and ion signaling pathways might be difficult in older organisms, suggesting a dysfunctional redox triangle may accompany the aging process.

Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum

“…Consistent with these reports, delivery of PBA to hepatoma cells exposed elevated palmitate increases non-mitochondrial oxygen consumption, promotes generation of ROS, and expands the ERQC. Thus, PBA-dependent recovery of ER function may involve increased protein turnover with excessive generation of ROS 50 . We find that, in diet-induced obesity, weight gain and hepatosteatosis were not reversed by treatment with the chemical chaperone PBA.…”

Diurnal Rhythms Spatially and Temporally Organize Autophagy

“…The dynamics of cluster 1 turnover were consistent in autophagosome number with previously published rhythms ( Ma et al, 2011 ). However, proteomics revealed a second autophagy rhythm (cluster 2), in which substrate preferences were directed toward mitochondria, ER, and peroxisomes, all ROS-generating structures that are known to physically interact ( Yoboue et al, 2018 ). Although these structures are thought to be targets of selective autophagy, the dynamics of cluster 2 protein degradation were not explained by known selective autophagy adaptor molecules (such as p62 and NBR1), whose turnover follows cluster 1.…”

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

“…ER and mitochondria are joined together with a specialized set of redox-sensitive proteins at specific domains, termed mitochondria-associated membranes (MAMs) [ 123 , 124 ]. Mitochondria–ER contacts play important roles in various functions, such as Ca 2+ handling, redox signaling, apoptosis, ER stress, and regulation of mitochondrial morphology.…”