One Ring to Rule Them All: Mitochondrial Circular RNAs Control Mitochondrial Function

Abstract

Circular RNAs (circRNAs) have emerged as key regulators of a wide variety of biological processes, but the roles of mitochondrial circRNAs are largely unknown. In this issue of Cell, Zhao et al. (2020) reveal that mitochondrial DNA-encoded circRNAs interact with ATP synthase subunit β (ATP5B) to inhibit the output of mitochondrial reactive oxygen species and the activation of liver fibroblasts, which regulate the pathogenesis of liver disease.

Figure 1.. circRNA SCAR Produced by mtDNA Suppresses mROS Output and Fibroblast Activation

In normal liver fibroblasts (left), peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha (PGC-1α) promotes the expression of circRNA steatohepatitis-associated circRNA ATP5B regulator (SCAR), which sequesters ATP synthase subunit β (ATP5B) and shuts down mitochondrial permeability transition pore (mPTP) by blocking cyclophilin D (CypD)-mPTP interaction. The closure of mPTP prevents the releasing of mitochondrial ROS (mROS) into the cytosol and inhibits fibroblast activation. In nonalcoholic steatohepatitis (NASH) fibroblasts (right), lipid-accumulation-induced ER stress increases the expression of C/EBP homologous protein (CHOP), which negatively regulates the expression of PGC-1α. Decreased PGC-1α expression reduces circRNA SCAR expression, which enables the release of its bound ATP5B protein. Free ATP5B promotes mPTP formation and facilitates the movement of mROS from the mitochondria into the cytosol. As a result, the increased cytosolic ROS (cROS) activates fibroblast and induces their pro-fibrotic and pro-inflammatory functions.