ROLE OF MICRORNAs IN REGULATING MITOCHONDRIAL BIOGENESIS AND FUNCTION

Abstract

Coordination between energy intake, storage, and expenditure is necessary for energy homeostasis. Variations in one of these processes are often balanced out in healthy individuals by control of the other two. On the other hand, metabolic disorders result from deviations from the improper balance of the caloric equation. A comprehensive investigation over the following century identified two key roles of mitochondria: producing ATP, the cell's energy currency, and creating biosynthetic intermediates to maintain energy homeostasis. This abstract summarized the findings from three independent studies linking the pivotal role of microRNA-128 (miR-128) in mitochondrial biogenesis and function as well as its implications for metabolic disorders. First, we had established a direct link between miR-128 and extensively described as a master regulator of mitochondrial biogenesis and oxidative phosphorylation PGC1α in vitro and in vivo. Overexpression of miR-128 in C2C12 myoblasts reduced mitochondrial biogenesis, altered dynamics, and impaired ATP production leading to mitochondrial dysfunction. Conversely, Inhibition of miR-128 expression improved mitochondrial health and oxidative phosphorylation. Second, we have tried to identify the key genes associated with mitochondrial function and their mRNA-miRNA network by employing an integrated approach of machine learning based feature selection and explainable artificial intelligence. We found BAX, a target of the miR-128 gene, as one of the top features in the study. We have previously shown the role of miR-128 in mitochondrial dysfunction by directly targeting BAX. In addition, the interaction network highlighted the regulatory role of miR-375, miR-30a 5p, miR-16-5p, miR-129-5p, miR-1229-3p, and miR-1224-3p, offering insights into novel therapeutic targets. Third, we have identified miR-128's potential as a regulator of BICD1 as a target, impacting intracellular transportation of HIF1α which correlates with reduced activity and affects mitochondrial metabolism. In summary, these studies collectively contributed to our understanding of the molecular mechanisms linked to miR-128, mitochondrial function, and metabolic disorders, offering insights into potential therapeutic targets and early intervention strategies for metabolic disorders like obesity and T2DM.