miR-30 Regulates Mitochondrial Fission through Targeting p53 and the Dynamin-Related Protein-1 Pathway

Abstract

miRNAs participate in the regulation of apoptosis. However, it remains largely unknown as to how miRNAs are integrated into the apoptotic program. Mitochondrial fission is involved in the initiation of apoptosis. It is not yet clear whether miRNAs are able to regulate mitochondrial fission. Here we report that miR-30 family members are able to regulate apoptosis by targeting the mitochondrial fission machinery. Our data show that miR-30 family members can inhibit mitochondrial fission and the consequent apoptosis. In exploring the underlying molecular mechanism, we identified that miR-30 family members can suppress p53 expression. In response to the apoptotic stimulation, the expression levels of miR-30 family members were reduced, whereas p53 was upregulated. p53 transcriptionally activated the mitochondrial fission protein, dynamin-related protein-1 (Drp1). The latter conveyed the apoptotic signal of p53 by initiating the mitochondrial fission program. miR-30 family members inhibited mitochondrial fission through suppressing the expression of p53 and its downstream target Drp1. Our data reveal a novel model in which a miRNA can regulate apoptosis through targeting the mitochondrial fission machinery.

Author Summary

Apoptosis is related to the pathogenesis of many diseases such as tumors and neurodegenerative and cardiovascular disorders. Apoptosis is controlled by a variety of genes, and among them a protein called “p53” has been taken as a “death star” and is involved in the initiation of apoptosis. The upstream and downstream molecules that control and convey p53 apoptotic function remain to be further identified. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Mitochondrial fission participates in the initiation of apoptosis and requires the activation of a protein called dynamin-related protein-1 (Drp1). Our present work has revealed that miR-30 can target p53, thereby inhibiting p53 expression. Furthermore, our data show that p53 is able to induce mitochondrial fission by transcriptionally regulating Drp1. In addition, miR-30 controls Drp1 activity and the consequent apoptosis through p53. Our findings may warrant future studies to explore the therapeutic approaches for apoptosis-related diseases by targeting the miR-30-p53-Drp1 pathway.