Genomic ncRNAs regulating mitochondrial function in neurodegeneration: a neglected clue in the complex etiopathogenesis of multiple sclerosis

Multiple sclerosis (MS), the most prevalent myelinopathy with unclear etiology, involves mitochondrial dysfunction that critically contributes to oligodendrocyte damage and neurodegeneration. Recent interest has surged around the role of inflammatory non-coding RNAs (ncRNAs) in mitochondrial function, particularly in the context of neurodegenerative diseases (NDs), where neuroinflammation is a hallmark feature. This review highlights the collection and characterization of mitochondrial-related ncRNAs (MRncRNAs) that have been extensively studied in the context of NDs. Through a literature review, we identified 35 MRncRNAs (23 miRNAs, 8 LncRNAs, and 4 circRNAs) across Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Notably, the inflammatory miRNAs miR-34a and miR-146a were commonly dysregulated in both PD and AD, while in HD, only a single miRNA, miR-196a, was identified. As expected, due to the mitochondrial nature of PD, the majority of MRncRNAs (9 miRNAs, 8 lncRNAs, and 3 circRNAs) were associated with this disorder. Further bioinformatic analysis of MRmiRNAs revealed that miR-124-5p, -146a-3p, and -15b-3p target mitochondrial genes more than others, and mRNA of pro-apoptotic protein BCL2L11 is the most targeted. Notably, the link between these MRncRNAs and mitochondrial function in MS remains unidentified. By evaluating upregulated MS-related ncRNAs in patients and comparing them with identified MRncRNAs, we found nine overlapping miRNAs (miR-15b, miR-21, miR-27b, miR-34a, miR-124, miR-137, miR-146a, miR-155, and miR-92a) as well as two shared lncRNAs, MALAT1 and HOTAIR (called MS/MRncRNAs). Further bioinformatic analysis of MS/MRmiRNAs revealed that the autophagy pathway is the most involved. Six of these miRNAs are significantly involved in MR diseases. Notably, miR-34a-5p showed a connection to oligodendrocyte mitochondria, while miR-15b targeted two MR hub genes, SDHC and BCL2. Moreover, several hub proteins (HIF1A, STAT3, MAPK1, GSK3B) targeted by these miRNAs are well-known regulators of inflammatory pathways and mitochondrial homeostasis: These findings highlight the critical roles of ncRNAs in mitochondrial dysfunction and neurodegeneration, emphasizing the urgent need for experimental studies on MRmiRNAs, particularly in the context of MS and other myelinopathies.