PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c

Asli E Dogan; Syed M Hamid; Asli D Yildirim; Zehra Yildirim; Ganes Sen; Celine E Riera; Roberta A Gottlieb; Ebru Erbay

doi:10.1016/j.jbc.2022.102050

PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c

J Biol Chem. 2022 Jul;298(7):102050. doi: 10.1016/j.jbc.2022.102050. Epub 2022 May 19.

Authors

Asli E Dogan¹, Syed M Hamid², Asli D Yildirim³, Zehra Yildirim¹, Ganes Sen⁴, Celine E Riera⁵, Roberta A Gottlieb⁶, Ebru Erbay⁷

Affiliations

¹ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular Biology and Genetics, National Nanotechnology Center, Bilkent University, Ankara, Turkey.
² Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
³ Department of Molecular Biology and Genetics, National Nanotechnology Center, Bilkent University, Ankara, Turkey.
⁴ Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵ Department of Biomedical Sciences, Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Neurology, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; David Geffen School of Medicine, University of California, Los Angeles, California, USA.
⁶ Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷ David Geffen School of Medicine, University of California, Los Angeles, California, USA; Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address: ebru.erbay@ucla.edu.

Abstract

The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.

Keywords: RNAi; brown adipose tissue; micro-RNA; mitochondria; mitochondrial biogenesis.

MeSH terms

Adipose Tissue, Brown* / metabolism
Animals
Electron Transport Complex I / metabolism
Mice
MicroRNAs* / genetics
Mitochondria*
Organelle Biogenesis*
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
RNA-Induced Silencing Complex / metabolism

Substances

MicroRNAs
Prkra protein, mouse
RNA-Binding Proteins
RNA-Induced Silencing Complex
mirn181 microRNA, mouse
Electron Transport Complex I

Grants and funding

R01 HL149972/HL/NHLBI NIH HHS/United States