Mitochondrial-Endoplasmic Reticulum Communication-Mediated Oxidative Stress and Autophagy

Abstract

Oxidative stress is an imbalance between free radicals and the antioxidant system causing overgeneration of free radicals (oxygen-containing molecules) ultimately leading to oxidative damage in terms of lipid peroxidation, protein denaturation, and DNA mutation. Oxidative stress can activate autophagy to alleviate oxidative damage and maintain normal physiological activities of cells by degrading damaged organelles or local cytoplasm. When oxidative stress is not eliminated by autophagy, it activates the apoptosis cascade. This review provides a brief summary of mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy. Mitochondria and endoplasmic reticulum being important organelles in cells are directly or indirectly connected to each other through mitochondria-associated endoplasmic reticulum membranes and jointly regulate oxidative stress and autophagy. The reactive oxygen species (ROS) produced by the mitochondrial respiratory chain are the main inducers of oxidative stress. Damaged mitochondria can be effectively cleared by the process of mitophagy mediated by PINK1/parkin pathway, Nix/BNIP3 pathways, and FUNDC1 pathway, avoiding excessive ROS production. However, the mechanism of mitochondrial-endoplasmic reticulum communication in the regulation of oxidative stress and autophagy is rarely known. For this reason, this review explores the mutual connection of mitochondria and endoplasmic reticulum in mediating oxidative stress and autophagy through ROS and Ca²⁺ and aims to provide part of the theoretical basis for alleviating oxidative stress through autophagy mediated by mitochondrial-endoplasmic reticulum communication.

Figure 1

Mitochondria-endoplasmic reticulum communication-mediated oxidative stress. When stimulated by starvation, hypoxia, etc., the ROS produced by the mitochondrial respiratory chain increases leading to oxidative stress. At the same time, ROS damages the Ca²⁺ channels in the endoplasmic reticulum and depletes the Ca²⁺ in the endoplasmic reticulum. The overload of Ca²⁺ in the mitochondria affects the production of ROS in the respiratory chain. In order to alleviate oxidative damage, mitochondria and endoplasmic reticulum can promote unfolded formation of spatial structure and misfolded proteolysis through unfolded protein reaction. (1) The accumulation of ROS and harmful proteins can activate JNK, thereby increasing the expression of CHOP and ATF5 transcription factors, encoding heat shock proteins and proteases that can hydrolyze misfolded proteins. (2) ROS increase the transcription of NRF1 by activating ERα, augment the expression of protease, and reduce oxidative damage. (3) Mitochondria can also enhance the levels of antioxidant enzymes SOD and CAT by activating the Sir3-FOXO3a pathway to protect cells from oxidative attacks. (4) Mitochondria can also improve the levels of antioxidant enzymes SOD and CAT by activating the Sir3-FOXO3a pathway to protect cells from oxidative attacks.

Figure 2

Mitochondria-endoplasmic communication-mediated autophagy. Mitochondria and endoplasmic reticulum can control the distance between the two organelles through PTPIP51 and VAPB protein, thereby affecting the Ca²⁺ exchange between mitochondria and endoplasmic reticulum. Ca²⁺ is the second messenger in cells, and its content can regulate the degree of oxidative stress and autophagy of mitochondria and endoplasmic reticulum. (1) When oxidative stress occurs, the mitochondrial membrane potential decreases, PINK/parkin pathway is activated, and membrane proteins are ubiquitinated. Ubiquitinated membrane proteins bind to LC3 and p62 to localize autophagosomes to damaged mitochondria. (2) Mitochondria can also activate ULK1 complex and PIK3C3 complex by phosphorylating Beclin1 and inhibiting mTOR to enhance the expression of autophagy genes and promote the formation of autophagosomes. (3) The FUNDC1 receptor on the mitochondrial membrane has a good affinity with ULK1 and can bind to it to induce mitochondrial autophagy. (4) The endoplasmic reticulum-unfolded protein response can phosphorylate eIF2α by activating PERK, thereby promoting the expression of autophagy-related genes and enhancing the transcription of CHOP, thereby recruiting autophagosomes. IRE1 can also increase the expression of CHOP transcription factors by activating JNK. ATF6 can upregulate the activity of death-related proteases, phosphorylate Beclin1, and induce autophagy. (5) Increased Ca²⁺ in the cytoplasm can activate CAMK2B, thereby activating AMPK and inhibiting the phosphorylation of mTOR. (6) The combination of FAM134B and LC3 accelerates the fragmentation of damaged endoplasmic reticulum and promotes the formation of autophagic membranes.