Science: new research reveals that VDAC protein oligomer promotes mitochondrial DNA release and autoimmune response

January 13, 2020 / bioin / - -- the immune system uses its mitochondria to self stimulate innate and adaptive responses to infection Active oxygen species (ROS), immunogenic mitochondrial DNA (mtDNA) and even the whole mitochondria are mobilized locally in a delicate balance, thus producing a hot spot of inflammatory effect When the normal restrictive feedback of these processes is destroyed, harmful autoimmune reactions often occur A common sign of abnormal immune system is the presence of anti mitochondrial antibody (AMA) in the blood For example, in systemic lupus erythematosus (SLE), AMA targeting multiple mitochondrial compartments can be found Some AMA targets proteins usually found in the outer mitochondrial membrane, while others target mtDNA One of the natural problems is how the immune system finds mtDNA released from mitochondria, given that mtDNA is normally located in the mitochondrial matrix To solve this problem, researchers from the national heart, lung and Blood Institute and other research institutions found in a new study that mtDNA released can cause lupus In short, when mitochondria are stressed in many ways, mtDNA breaks into fragments and binds to voltage dependent anion channels (VDAC) in the outer membrane of mitochondria This leads to the aggregation of VDAC monomers and the formation of a meta pore in the middle of them, through which mtDNA can escape Once in the cytoplasm, a variety of non-specific sensing proteins, including Toll receptor for single stranded DNA and gas-sting pathway for double stranded DNA, trigger mature type I interferon (IFN) response The related research results were recently published in the Journal of science The title of the paper is "VDAC oligors form mitochondrial pools to release mtDNA fragments and promote lupus like disease" The oligomerization of 0I a Vdac1 forms a hole for mtDNA to pass through The picture is from jeonghan Kim et al National Heart Lung and Blood Institute, Bethesda, MD Each VDAC monomer itself contains a highly regulated channel, which allows key molecules of different sizes and charges to pass in any direction according to the current membrane potential It is not feasible to completely eliminate VDAC function in higher eukaryotes Fortunately, the researchers found that blocking only one of these channels, Vdac1, with the oligomerization inhibitor vbit-4, eliminated the immune activation that led to lupus like symptoms Discoid lupus erythematosus is the skin form of lupus erythematosus, which is often associated with systemic lupus erythematosus As a general treatment strategy, interference with mtDNA release alone may not completely clear all AMA in patients However, this approach may be more useful for other forms of lupus, such as lupus nephritis, because all AMA found appear to target double stranded mtDNA Other types of autoimmune diseases, such as those affecting the liver and bile ducts, may also be associated with AMA Primary biliary cholangitis and primary sclerosing cholangitis are two diseases characterized by different forms of autoantibodies Sclerosing cholangitis is associated with antinuclear antibody (ANA) On the other hand, cholangitis patients have AMA targeting at the E2 subunit of pyruvate dehydrogenase complex In addition, these patients usually have antibodies targeting sulfite oxidase and glycogen phosphorylase related to liver mitochondria At present, it is not clear how and where these specific types of antibodies are produced This immunogenic E2 subunit usually floats in the mitochondrial matrix together with mitochondrial DNA and does not habitually escape through any channel It is speculated that the abnormal fragments produced by mitochondrial degradation of dying cells may contribute to the formation of autoantibodies In the process of trying to understand the production of AMA, a prominent problem that these researchers have ignored so far is how mtDNA reaches the outer membrane VDAC through the inner membrane of mitochondria Peggy crow of New York Special Surgery Hospital pointed out that although the exact answer is not clear, the imaging study shows another pore system which works in parallel with VDAC These so-called "bak / Bax macropores" allow the mitochondrial inner membrane to protrude into the cytoplasm, penetrate and transport matrix components including mtDNA So far, these researchers have not talked about the active oxygen factor in mitochondrial inflammation Their other discovery has linked oligomerization of Vdac1 channels to ROS More specifically, they found a molecule called lipoxstatin-1 that protects cells from reactive oxygen species by lowering the levels of vda1 and GPx4, the recovery enzyme GPx4 is a unique selenium utilization form of glutathione peroxidase, which can specifically protect lipid in cell membrane from oxidative damage When GPx4 is damaged, a unique form of apoptosis occurs in the whole cell, namely iron death By blocking the oligomerization of Vdac1 instead of Vdac2 or vdac3, they found that liproxstein-1 could short-circuit the iron death pathway Importantly, lipoxstatin-1 can also block the contraction of mitochondria, the reduction and destruction of cristae in mitochondria, and other mitochondrial membrane breaks that lead to iron death GPx4 deficiency is not an autoimmune disease, but a disease characterized by uncontrolled ROS damage and iron death in a very limited cell population The disease is so rare - it's so rare, in fact, that the newly diagnosed patient is the only one in the world with the mysterious disease (BIOON Com) reference: 1 Jeonghan Kim et al VDAC oligors form mitochondrial pools to release mtDNA fragments and promote lupus like disease Science, 2019, DOI: 10.1126/science.aav4011 2 Mary K crow Mitochondrial DNA promotes automation Science, 2019, doi:10.1126/science.aaz9308 3.Know thy mitochondria: Autoimmunity to organelles and their DNA 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