Jeonghan Kim (National Institutes of Health)| Heeeun Yoon (National Institutes of Health)| Jay Chung (National Institutes of Health)
Stressed mitochondria can release mitochondrial DNA (mtDNA) into the cytosol via the mitochondrial outer membrane (MOM), where it interacts with and activates a large number of immunostimulatory DNA sensors, which can promote inflammation and metabolic disorders. The voltage-dependent anion channel (VDAC), which in the mammalian mitochondria is represented by three isoforms (VDAC1, VDAC2, and VDAC3), is the most abundant protein in the MOM and regulates metabolism, inflammasome activation, and the type-I interferon signaling pathway. We found that VDAC-mediated cytosolic mtDNA release can activate the type-I interferon signaling pathway and cause obesity and autoimmune diseases such as systemic lupus erythematosus (SLE). The VDAC oligomerization inhibitor VBIT-4 decreases both adipogenesis and weight gain in leptin-deficient (ob/ob) mice. Also, in a mouse model of lupus, VBIT-4 ameliorated lupus-like symptoms through diminishing mtDNA release and NETosis. Our findings support VDAC oligomerization as a new therapeutic target for obesity and inflammatory disease associated with mtDNA release.