Bioengineered miR-34a targets MPV17L2 to control cancer cell mitochondrial functions.

MicroRNAs (miRNA or miR) are small noncoding RNAs derived from the genome to control posttranscriptional gene expression critical for various cellular processes. Recently we have invented a novel platform technology that offers high-yield production of humanized, bioengineered miRNA agents (hBERAs) for research and development. This study is aimed to produce and utilize a novel biologic miR-34a-5p (or miR-34a) molecule, namely hBERA/miR-34a, to delineate the role of miR-34a-5p in the regulation of mitochondrial functions in carcinoma cells. Bioengineered hBERA/miR-34a was selectively processed to target miR-34a-5p in human osteosarcoma and lung cancer cells. The mitochondrial inner membrane protein MPV17 like 2 (MPV17L2) was identified and validated as a new direct target for miR-34a-5p. Furthermore, we demonstrated that miR-34a-5p-controlled MPV17L2 protein downregulation significantly inhibited respiratory chain complex I assembly and activities as well as intracellular ATP levels. Consequently, biologic miR-34a-5p treatment sharply reduced cancer cell mitochondrial respiration, increased oxidative stress, and elevated apoptotic cell death. These results demonstrate an important role of miR-34a-5p-MPV17L2 pathway in the control of mitochondrial functions in carcinoma cells and support the utility of novel bioengineered miRNA molecules for functional studies.