The Pathophysiological Roles of Mirna in Mitochondrial Diseases

Micro RNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that serve as crucial post-transcriptional gene regulators for cell proliferation and development. Recently, miRNAs were found to target and present specifically in mitochondria to regulate in a direct manner genes coding for mitochondrial proteins, and consequently mitochondrial function and related diseases. However, how miRNAs play regulatory roles in the pathophysiological outcome of respiratory chain (RC) defect-associated mitochondrial stresses in human diseases remains unelucidated. This study, thus, aims to 1) identify how RC defect-associated mitochondrial stresses alter the levels of miRNAs, 2) mechanistically elucidate how each evaluated miRNAs alter the pathophysiological outcome of RC defect-associated mitochondrial stresses and diseases, and 3) explore the bioavailability of mitochondria-targeted protectors for the prevention and treatment of miRNA-associated mitochondrial stresses and human mitochondrial diseases. First, RC defect-associated miRNAs alteration will be identified using miRNA array in control and RC defect cells. With the application of fluorescent probes coupled multi-photon laser scanning digital imaging microscopy, miRNA-associated mitochondrial pro- and anti-apoptotic stresses will be elucidated precisely. We proposed miRNAs levels interact closely with RC defect-associated mitochondrial stresses including mitochondrial reactive oxygen species generation and mitochondrial Ca2+ regulation to remodel cardiolipin-mediated mitochondrial dynamics of fission and fusion and hence triggering the mitochondrial permeability transition and finally autophagy of mitochondrion (mitophagy). The genetic up or down regulation of specific miRNAs and pharmacological maneuvers thus may effectively protect and prevent specific miRNA-mediated mitochondrial stresses. The precise elucidation of pathophysiological regulation as well as therapeutic strategies of miRNA-mediated RC defect-associated mitochondrial stresses can be critical for future optimizing the prevention and treatment of miRNA-mediated RC defect-associated mitochondrial pathologies in human mitochondrial diseases.

Project ID:PC10608-2359
External Project ID:MOST106-2320-B182-001