Fast Degradation of MecciRNAs by SUPV3L1/ELAC2 Provides a Novel Opportunity to Tackle Heart Failure With Exogenous MecciRNA

BACKGROUND: Circular RNAs derived from both nuclear and mitochondrial genomes are identified in animal cells. Mitochondria-encoded circular RNAs (mecciRNAs) are attracting more attention, and several members of mecciRNAs have already been recognized in regulating mitochondrial functions. Mitochondria dysfunctions are well-known to participate in heart failure (HF). This study was designed to investigate the RNA metabolism of mecciRNAs and the relevant roles and potential application of mecciRNAs in HF. METHODS: Compared with highly stable nuclear genome-encoded circular RNAs, the fast degradation feature of mecciRNAs is identified by RNA sequencing and a series of molecular, biochemical, and cellular experiments. The substantial protective effects of in vitro synthesized mecciRNAs were tested in both doxorubicin- and pressure overload–induced mouse models of HF. RESULTS: We discover that mecciRNAs are promptly degraded by an animal-conserved complex of helicase SUPV3L1 (suppressor of var1, 3-like protein 1) and endoribonuclease ELAC2 (elaC ribonuclease Z 2). MecciRNA degradation complex and mecciRNAs interact with mitochondrial permeability transition pore and its regulators including TRAP1 (TNF receptor–associated protein 1) and CypD (cyclophilin D). MecciRNAs regulate mitochondrial levels of TRAP1 and CypD to modulate the opening of mitochondrial permeability transition pore and the release of mitochondrial reactive oxygen species. Exogenously applied mecciRNAs interact with cytosolic TRAP1 and increase mitochondrial levels of TRAP1, and lead to a more closed state of mitochondrial permeability transition pore to constrain deleterious reactive oxygen species release. HF conditions lead to stimulated mecciRNA degradation, and administration of in vitro synthesized mecciRNAs exhibits substantial protective effects in both doxorubicin- and pressure overload–induced mouse models of HF. CONCLUSIONS: This study demonstrates the fast degradation of mecciRNAs and the associated regulations of mitochondrial reactive oxygen species release of mitochondrial permeability transition pore by mecciRNAs. HF conditions lead to dysregulated mecciRNA degradation, and exogenous mecciRNAs demonstrate treatment potential in mouse models of HF.