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Published on: June 11, 2020
Fast Degradation of MecciRNAs by SUPV3L1/ELAC2 Provides a Novel Opportunity to Tackle Heart Failure With Exogenous
Xu Liu1, Qinwei Wang1, Xinya Li1
1Department of Cardiology, Department of Laboratory Medicine, First Affiliated Hospital of University of Science and Technology of China, RNA Institute, School of Basic Medical Sciences, Division of Life Science and Medicine (X. Liu, Q.W., X. Li, Y.Y., Y.D., X.W., L.C., L.M., G.S.), University of Science and Technology of China, Hefei.
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.
Insights
Mitochondria-encoded circular RNAs (mecciRNAs) are rapidly degraded and regulate mitochondrial function. Supplementing mecciRNAs protected against heart failure in mouse models, showing therapeutic potential.
Area of Science:
- Mitochondrial biology
- RNA metabolism
- Cardiovascular research
Background:
- Circular RNAs (circRNAs) exist in nuclear and mitochondrial genomes.
- Mitochondria-encoded circRNAs (mecciRNAs) regulate mitochondrial functions.
- Mitochondrial dysfunction is implicated in heart failure (HF).
Purpose of the Study:
- Investigate mecciRNA metabolism and function in HF.
- Explore the therapeutic potential of mecciRNAs for HF.
Main Methods:
- Identified mecciRNA degradation via RNA sequencing and molecular experiments.
- Assessed protective effects of synthesized mecciRNAs in HF mouse models.
- Utilized doxorubicin and pressure overload to induce HF.
Main Results:
- Discovered mecciRNA degradation by SUPV3L1 and ELAC2 complex.
- MecciRNAs modulate mitochondrial permeability transition pore (mPTP) opening.
- Exogenous mecciRNAs protect against HF by regulating mPTP and reactive oxygen species (ROS).
Conclusions:
- MecciRNAs are rapidly degraded and regulate mPTP-mediated ROS release.
- HF stimulates mecciRNA degradation.
- Exogenous mecciRNAs show therapeutic potential for HF in mouse models.
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