miR-140-5p Overexpression Contributes to Oxidative Stress and Mitochondrial Dysfunction in Hutchinson-Gilford...

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disorder characterized by accelerated aging. The accumulation of an abnormal and toxic protein called progerin within HGPS nuclei disrupts cellular processes, including gene expression and DNA repair. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defense, is one of the hallmarks of HGPS. To identify novel molecular mechanisms underlying HGPS pathogenesis, we performed miRNA expression profiling in HGPS compared to healthy control fibroblasts. We identified 10 differentially expressed (DE) miRNAs between HGPS and control cells. We focused on miR-140-5p and miR-140-3p, 2 miRNAs upregulated in HGPS fibroblasts. miR-140-5p is known to directly target the transcript of NRF2, a master regulator of the antioxidant response. Using in vitro mimic and antimiR transfections, we demonstrated that miR-140-5p overexpression in HGPS fibroblasts results in the downregulation of the NRF2/KEAP1/HO-1 antioxidant pathway, leading to increased oxidative stress. Furthermore, our results indicate that miR-140-5p overexpression induces mitochondrial dysfunction, characterized by a reduced oxidative phosphorylation capacity and affects other hallmarks of aging. By targeting regulation of oxidative stress and mitochondrial function through NRF2, miR-140-5p may play a pivotal role in the pathophysiology of HGPS and open new therapeutic avenues.