miR-29a-3p and TGF-beta Axis in Fanconi Anemia: Mechanisms Driving Metabolic Dysfunction and Genome Stability

Abstract

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and cancer susceptibility due to defective DNA double-strand break repair. However, FA cells are also characterized by mitochondrial dysfunction and redox imbalance. To identify a common factor among these alterations, we focused on miR-29a-3p, a microRNA involved in hematopoiesis. Our data show that miR-29a-3p is downregulated in lymphoblasts and fibroblasts mutated for the FANC-A gene, causing the overexpression of its target genes, FOXO3, SGK1, and IGF1, which results in PI3K/AKT pathway hyperactivation, altered mitochondrial metabolism and insufficient antioxidant response. Furthermore, miR-29a-3p downregulation appears associated with hyperactivation of the TGF-{beta} signal. However, restoring miR-29a-3p expression improves mitochondrial metabolism, oxidative stress response, and DNA damage repair by inhibiting the PI3K/AKT pathway and modulating TGF-{beta} signaling by a feedback mechanism. Based on these findings, miR-29a-3p appears as a promising molecular target to address several mechanisms based on FA pathogenesis.