The Role of MicroRNAs in Mitochondria-Mediated Eye Diseases

Abstract

The retina is among the most metabolically active tissues with high-energy demands. The peculiar distribution of mitochondria in cells of retinal layers is necessary to assure the appropriate energy supply for the transmission of the light signal. Photoreceptor cells (PRs), retinal pigment epithelium (RPE), and retinal ganglion cells (RGCs) present a great concentration of mitochondria, which makes them particularly sensitive to mitochondrial dysfunction. To date, visual loss has been extensively correlated to defective mitochondrial functions. Many mitochondrial diseases (MDs) show indeed neuro-ophthalmic manifestations, including retinal and optic nerve phenotypes. Moreover, abnormal mitochondrial functions are frequently found in the most common retinal pathologies, i.e., glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), that share clinical similarities with the hereditary primary MDs. MicroRNAs (miRNAs) are established as key regulators of several developmental, physiological, and pathological processes. Dysregulated miRNA expression profiles in retinal degeneration models and in patients underline the potentiality of miRNA modulation as a possible gene/mutation-independent strategy in retinal diseases and highlight their promising role as disease predictive or prognostic biomarkers. In this review, we will summarize the current knowledge about the participation of miRNAs in both rare and common mitochondria-mediated eye diseases. Definitely, given the involvement of miRNAs in retina pathologies and therapy as well as their use as molecular biomarkers, they represent a determining target for clinical applications.

Regulations of Retinal Inflammation: Focusing on Müller Glia

“…In the eyes, miRNAs not only actively participate in the cell fate determination in the retinal development ( Cremisi, 2013 ), but also regulate the differentiation potential of the MG ( Quintero and Lamas, 2018 ). Besides, miRNAs participate in the pathogenesis of multiple diseases, including Leber hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (ADOA), glaucoma, DR, and AMD ( Zuzic et al, 2019 ; Carrella et al, 2021 ). The miRNA expression profile of mouse MG in vivo reveals that miR-204, miR-9, and miR-125-5p are the ones highly expressed by MG but low in neurons ( Wohl and Reh, 2016 ).…”

miR ‐181a/b downregulation: a mutation‐independent therapeutic approach for inherited retinal diseases

“…Degeneration of photoreceptors (PRs) is the common landmark in IRDs even though a precise knowledge of the underlying molecular and cellular events is still far from reach. Among the most relevant pathways involved, mitochondrial dysfunction, neuroinflammation, and microglia activation are known to worsen PR death and accelerate disease progression (Ambati et al , 2013; Cuenca et al , 2014; Zhao et al , 2015; Lefevere et al , 2017; Mirra & Marfany, 2019; Carrella et al , 2021). Targeting key effectors that impact on common dysregulated pathways in neuronal damage during disease progression hold great promise for therapeutic purposes (Indrieri et al , 2019; Carrella et al , 2020).…”

“…Over the last decades, evidence linking mitochondrial dysfunction to IRDs is increasing (Carrella et al , 2021). The outer retina is known to have a high metabolic demand, which is associated with abundance of mitochondria in the retinal pigment epithelium (RPE) and PRs.…”

“…The latter cells are under constant environmental challenges and are highly prone to oxidative stress, a major contributor to retinal degenerations and hence IRDs (Lefevere et al , 2017; Mirra & Marfany, 2019; Jiang et al , 2022). Importantly, since mitochondrial dysfunction seems to be an early event in IRDs, approaches targeting basic mitochondrial functions hold great therapeutic promise (Lefevere et al , 2017; Carrella et al , 2021).…”

Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

“…Oxidative stress has been noted as an important chronic stressor contributing to retinal damage in patients with RP. Indeed, recent studies have discovered that exposure to oxidative stress determines the altered expression of micro-RNA and long non-coding RNA that is likely implicated in the pathogenesis and progression of RP [42].…”