Mitochondrial ncRNAs Emerge as Key Regulators and Targeted Therapeutic Candidates in Heart Failure

Heart failure (HF) is intricately linked to mitochondrial dysfunction, characterized by abnormal energy metabolism, excessive reactive oxygen species (ROS) production, and imbalanced mitochondrial dynamics. Current clinical approaches often fall short in directly addressing these mitochondrial pathologies, leading to disease progression and multi-organ injury. This gap highlights the urgent need for novel, targeted therapies that can restore mitochondrial health. Mitochondrial non-coding RNAs (mt-ncRNAs) represent a crucial, yet underexplored, regulatory network governing mitochondrial function, offering a promising avenue for intervention.

This comprehensive review synthesized current research on the roles of mitochondrial non-coding RNAs (mt-ncRNAs) in the pathogenesis of Heart Failure (HF) and explored their potential as therapeutic targets. The authors focused specifically on two prominent classes: mitochondrial-encoded circular RNAs (mecciRNAs) and mitochondrial double-stranded RNAs (mt-dsRNAs). The review systematically analyzed existing literature detailing how these mt-ncRNAs regulate mitochondrial function, their involvement in HF progression, and the emerging strategies for their therapeutic manipulation, including gene therapy and targeted mitochondrial delivery approaches.

The review elucidated the distinct, yet interconnected, roles of mecciRNAs and mt-dsRNAs in Heart Failure (HF). mecciRNAs were identified as protective agents, primarily by assisting protein import into mitochondria, regulating mitochondrial pores, and modulating ROS levels. Their degradation was consistently linked to worsening HF, while exogenous supplementation demonstrated the ability to alleviate cardiac injury in preclinical models. Conversely, mt-dsRNAs were found to arise from aberrant mitochondrial transcription and actively contribute to myocardial injury and remodeling. This detrimental effect is mediated through activation of key innate immune pathways, including MAVS, cGAS-STING, and PNPT1. The authors highlighted that the precise modulation of these mt-ncRNAs offers a novel therapeutic strategy. > Gene therapy targeting mecciRNAs and mt-dsRNAs, combined with advanced mitochondrial delivery systems, represents a highly promising and innovative approach for future HF treatment.