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 ncRNAs in mitochondrial function, particularly in the context of neurodegenerative diseases (NDs) where neuroinflammation is a hallmark feature. This review emphasizes a collection and characterization of mitochondrial-related (MR) non-coding RNAs (ncRNAs) (MRncRNAs), that have been extensively studied in the context of NDs. Through a literature review, we identified 36 upregulated MRncRNAs in Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (ALZ), and Huntington's disease (HD). Notably, inflammatory miR-34 was the most dominantly dysregulated miR in PD, ALS, and ALZ while in HD, two other miRNAs (miR-10b-5p and miR-196a) have been identified. Further bioinformatic analysis of dysregulated miRNAs 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 ncRNAs and mitochondrial function in MS remains unidentified. Among the 81 upregulated ncRNAs detected in MS patients, we identified nine (miR-15b, miR-21, miR-27b, miR-34a, miR-124, miR-137, miR-146a, miR-155, and miR-92a) shared inflammatory miRNAs and two lncRNAs (MALAT1 and HOTAIR). Further bioinformatic analysis of miRNAs 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.