Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.

Keywords: microRNAs; mitochondria; neurodegenerative disorders.

Figure 1

Schematic representation of mitomiR biogenesis. The majority of miRNAs are transcribed in the nucleus and then transported to the cytoplasm as pre-miRNAs. Further, mature miRNAs are generated upon cytoplasmic processing of pre-miRNA. Certain miRNAs are translocated to the mitochondria through different mechanisms. Additionally, some mitomiRs can originate from mtDNA. Created with BioRender.com. Ago, Argonaute; DGCR8, Di George critical region 8; Exp5, exportin 5; mitomiR, mitochondrial miRNA; mtDNA, mitochondrial DNA; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA; SAM50, sorting and assembly machinery 50; TIM, translocase of the inner membrane; TOM20, translocase of the outer membrane 20; TRBP, transactivation response RNA-binding protein.

Figure 2

Recent evidence on the role of miR-107 in AD pathogenesis. Reduced miR-107 levels in the temporal cortex of patients with AD correlate with mitochondrial alterations. Suppressing miR-107 leads to a decline in mitochondrial membrane potential, whereas therapeutic restoration of miR-107 levels using a mimic reverses Aβ-induced AD-like symptoms in mouse models. Created with BioRender.com.

Figure 3

A summary of the influence of miR-34b/c depletion on mitochondrial function and PD development. Reduced miR-34b/c levels impair mitochondrial activity in differentiated SH-SY5Y cells, leading to increased oxidative stress and lower cellular ATP content. Downregulation of miR-34b/c is also associated with reduced expression of parkin and DJ-1, which are implicated in various forms of PD. Created with BioRender.com.

Figure 4

Role of miR-335-5p in ALS pathogenesis and mitochondrial regulation. MiR-335-5p dysregulation was observed in SH-SY5Y cells. Its depletion disrupts mitophagy, alters autophagy processes, and activates caspase 3/7-mediated apoptosis. These deficiencies contribute to the progressive loss of neuronal and muscle cell functioning, exacerbating ALS pathology. Created with BioRender.com.