The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity

J Biol Chem. 2020 Jan 10;295(2):444-457. doi: 10.1074/jbc.RA119.010511. Epub 2019 Nov 25.

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that suppress the expression of multiple genes and are involved in numerous biologic functions and disorders, including human diseases. Here, we report that two miRNAs, miR-302b and miR-372, target mitochondrial-mediated antiviral innate immunity by regulating mitochondrial dynamics and metabolic demand. Using human cell lines transfected with the synthetic analog of viral dsRNA, poly(I-C), or challenged with Sendai virus, we found that both miRNAs are up-regulated in the cells late after viral infection and ultimately terminate the production of type I interferons and inflammatory cytokines. We found that miR-302b and miR-372 are involved in dynamin-related protein 1 (DRP1)-dependent mitochondrial fragmentation and disrupt mitochondrial metabolism by attenuating solute carrier family 25 member 12 (SLC25A12), a member of the SLC25 family. Neutralizing the effects of the two miRNAs through specific inhibitors re-established the mitochondrial dynamics and the antiviral responses. We found that SLC25A12 contributes to regulating the antiviral response by inducing mitochondrial-related metabolite changes in the organelle. Structure-function analysis indicated that SLC25A12, as part of a prohibitin complex, associates with the mitochondrial antiviral-signaling protein in mitochondria, providing structural insight into the regulation of the mitochondrial-mediated antiviral response. Our results contribute to the understanding of how miRNAs modulate the innate immune response by altering mitochondrial dynamics and metabolic demand. Manipulating the activities of miR-302b and miR-372 may be a potential therapeutic approach to target RNA viruses.

Keywords: RNA virus; innate immunity; metabolic regulation; microRNA (miRNA); mitochondria; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate
  • MicroRNAs / immunology
  • MicroRNAs / metabolism*
  • Mitochondria / immunology
  • Mitochondria / metabolism*
  • Mitochondria / virology
  • Mitochondrial Membrane Transport Proteins / immunology
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / immunology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / virology
  • Respirovirus Infections / immunology
  • Respirovirus Infections / metabolism*
  • Respirovirus Infections / virology
  • Sendai virus / immunology
  • Sendai virus / physiology*

Substances

  • MIRN302A microRNA, human
  • MIRN372 microRNA, human
  • MicroRNAs
  • Mitochondrial Membrane Transport Proteins
  • SLC25A12 protein, human