Fast Degradation of MecciRNAs by SUPV3L1/ELAC2 Provides a Novel Opportunity to Tackle Heart Failure With Exogenous MecciRNA.
Summary
The study identifies a conserved SUPV3L1/ELAC2 complex that rapidly degrades mitochondrial circular RNAs, which regulate mitochondrial permeability transition pore and ROS via TRAP1 and CypD. In two mouse heart failure models, exogenous mecciRNAs increased TRAP1, reduced detrimental ROS release, and conferred cardioprotection, revealing a novel RNA-therapeutic avenue.
Key Findings
- MecciRNAs undergo rapid degradation by a conserved SUPV3L1 (helicase)/ELAC2 (endoribonuclease) complex.
- MecciRNAs regulate mPTP opening and mitochondrial ROS via interactions affecting TRAP1 and CypD levels.
- Exogenous mecciRNAs increased TRAP1 and reduced ROS, conferring cardioprotection in doxorubicin and pressure overload mouse HF models.
Clinical Implications
While preclinical, targeting mecciRNA degradation or delivering therapeutic mecciRNAs could complement existing heart failure treatments by directly modulating mitochondrial injury pathways.
Why It Matters
Reveals a previously unrecognized RNA degradation node controlling mitochondrial injury responses and provides proof-of-concept that exogenous mecciRNAs can mitigate heart failure injury.
Limitations
- Preclinical mouse and cellular models; translational delivery, dosing, and long-term safety of mecciRNA therapy remain untested in humans.
- Potential off-target effects and biodistribution of exogenous RNA require rigorous evaluation.
Future Directions
Develop delivery platforms for mecciRNAs, define pharmacokinetics/safety, and explore small-molecule or antisense strategies to modulate SUPV3L1/ELAC2 or TRAP1/CypD axes.
Study Information
- Study Type
- Case series
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic and therapeutic experiments in animal and cellular models.
- Study Design
- OTHER