Micrornas Fine-Tune Respiratory Chain Defect-Augmented Mitochondrial Pathological Outcomes in Mitochondrial Diseases

Micro RNAs (miRNAs) are a diverse family of short, single-stranded, non-coding RNA molecules that serve crucial roles in post-transcriptional gene regulation and cell functions. Using miRNA array, our previous grant identified levels of miRNAs fluctuated between normal and respiratory chain (RC) defects preparations. For instance, there are at least 7 miRNAs (miR-A~G) fluctuate significantly between control 143B osteosarcoma line and RC defect line of neuropathy, ataxia, retinitis pigmentosa (NARP) cybrid harboring mtDNA T8993G point mutation for the complex V inhibition. Mechanical elucidation using fluorescent probes coupled multi-photon laser scanning digital imaging microscopy, we observed miR-A significantly protects against RC defect-associated mitochondrial stresses. Thus, in the current grant we propose to investigate in detail how each miRNA fine-tunes RC defect-augmented mitochondrial pathological outcomes in mitochondrial diseases. Preparations with differential degrees of RC defects will be performed to mimic clinical conditions of single and dual RC defects by the application of complex inhibitors in 143B cells or using genetic disease origin cybrids such as the NARP cybrid for single complex inhibition and by using complex inhibitors I-IV in NARP cybrid to obtain dual RC complex inhibition. We aim to elucidate precisely how miRNAs fine-tune RC defect-augmented 1) mCa2+ stress and hence mCa2+-mediated mROS formation, ?m depolarization, 2) cardiolipin-mediated transition between the t-MPT and p-MPT, 3) dynamics of fission and fusion of mitochondria and mitochondrial movement and 4) mCa2+ and cardiolipin-mediated mitophagy. Lastly, the bioavailability of mitochondria-targeted miRNAs for the prevention and treatment of RC-augmented mitochondrial stresses and diseases will be explored. The precise elucidation of pathophysiological regulation as well as therapeutic strategies of miRNA-mediated RC defect-augmented mitochondrial pathological outcomes can be critical for future prevention and treatment of miRNA-mediated human mitochondrial diseases.

Project ID:PC10708-1062
External Project ID:MOST107-2320-B182-018