title: hsa-miR-4485 regulates mitochondrial functions and inhibits the tumorigenicity of breast cancer cells.
abstract: The modulation of mitochondrial functions is important for maintaining cellular homeostasis. Mitochondria essentially depend on the import of RNAs and proteins encoded by the nuclear genome. MicroRNAs encoded in the nucleus can translocate to mitochondria and target the genome, affecting mitochondrial function. Here, we analyzed the role of miR-4485 in the regulation of mitochondrial functions. We showed that miR-4485 translocated to mitochondria where its levels varied in response to different stress conditions. A direct binding of miR-4485 to mitochondrial 16S rRNA was demonstrated. MiR-4485 regulated the processing of pre-rRNA at the 16S rRNA-ND1 junction and the translation of downstream transcripts. MiR-4485 modulated mitochondrial complex I activity, the production of ATP, ROS levels, caspase-3/7 activation, and apoptosis. Transfection of a miR-4485 mimic downregulated the expression of regulatory glycolytic pathway genes and reduced the clonogenic ability of breast cancer cells. Ectopic expression of miR-4485 in MDA-MB-231 breast carcinoma cells decreased the tumorigenicity in a nude mouse xenograft model. Furthermore, levels of both precursor and mature miR-4485 are decreased in tumor tissue of breast cancer patients. We conclude that the mitochondria-targeted miR-4485 may act as a tumor suppressor in breast carcinoma cells by negatively regulating mitochondrial RNA processing and mitochondrial functions.
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Sripada
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Kritarth
authors.initials: K
authors.lastname: Singh
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Anastasiya V
authors.initials: AV
authors.lastname: Lipatova
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.
authors.forename: Aru
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Prajapati
authors.affiliation: Center for Translational Medicine, Temple University, Philadelphia, PA, 19140, USA.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Khyati
authors.initials: K
authors.lastname: Bhatelia
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Milton
authors.initials: M
authors.lastname: Roy
authors.affiliation: Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382007, India.
authors.forename: Rochika
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Chumakov
authors.affiliation: Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390002, India. singhraj1975@gmail.com.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D012336:RNA, Ribosomal, 16S / Q000378:metabolism*; D057900:Transcytosis
chemical_list: D035683:MicroRNAs; D012336:RNA, Ribosomal, 16S
keywords: Breast cancer; Mitochondria; Mouse xenograft; RNA processing; Tumor suppressors; miR-4485