PMID- 32073141
OWN - NLM
STAT- MEDLINE
DCOM- 20200917
LR  - 20200917
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 251
IP  - 1
DP  - 2020 May
TI  - A transgenic mouse expressing miR-210 in proximal tubule cells shows 
      mitochondrial alteration: possible association of miR-210 with a shift in energy 
      metabolism.
PG  - 12-25
LID - 10.1002/path.5394 [doi]
AB  - Previously we reported that the microRNA miR-210 is aberrantly upregulated in 
      clear cell renal cell carcinoma (ccRCC) via deregulation of the VHL-HIF pathway. 
      In the present study, to investigate the biological impact of miR-210 in ccRCC 
      tumorigenesis, we developed a transgenic mouse line expressing miR-210 in 
      proximal tubule cells under control of the mouse SGLT2/Slc5a2 promoter. Light 
      microscopy revealed desquamation of the tubule cells and regeneration of the 
      proximal tubule, suggesting that miR-210 expression led to damage of the proximal 
      tubule cells. Electron microscopy revealed alterations to the mitochondria in 
      proximal tubule cells, with marked reduction of the mitochondrial inner membrane, 
      which is the main site of ATP production via oxidative phosphorylation (OxPhos). 
      An additional in vitro study revealed that this loss of the inner membrane was 
      associated with downregulation of Iscu and Ndufa4, the target genes of miR-210, 
      suggesting that the miR-210-ISCU/NDUFA4 axis may affect mitochondrial energy 
      metabolism. Furthermore, metabolome analysis revealed activation of anaerobic 
      glycolysis in miR-210-transfected cells, and consistent with this the secretion 
      of lactate, the final metabolite of anaerobic glycolysis, was significantly 
      increased. Lactate concentration was higher in the kidney cortex of transgenic 
      mice relative to wild-type mice, although the difference was not significant 
      (p = 0.070). On the basis of these findings, we propose that miR-210 may induce a 
      shift of energy metabolism from OxPhos to glycolysis by acting on the 
      mitochondrial inner membrane. In addition to activation of glycolysis, we 
      observed activation of the pentose phosphate pathway (PPP) and an increase in the 
      total amount of amino acids in miR-210-transfected cells. This may help cells 
      synthesize nucleotides and proteins for building new cells. These results suggest 
      that miR-210 may be involved in the metabolic changes in the early stage of ccRCC 
      development, helping the cancer cells to acquire growth and survival advantages. 
      (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley 
      & Sons, Ltd.
CI  - (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley 
      & Sons, Ltd.
FAU - Nakada, Chisato
AU  - Nakada C
AUID- ORCID: 0000-0002-4172-2814
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
AD  - Department of Urology, Faculty of Medicine, Oita University, Yufu City, Japan.
FAU - Hijiya, Naoki
AU  - Hijiya N
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Tsukamoto, Yoshiyuki
AU  - Tsukamoto Y
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Yano, Shinji
AU  - Yano S
AD  - Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Kai, Tomoki
AU  - Kai T
AD  - Department of Urology, Faculty of Medicine, Oita University, Yufu City, Japan.
FAU - Uchida, Tomohisa
AU  - Uchida T
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Kimoto, Mami
AU  - Kimoto M
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Takahashi, Mika
AU  - Takahashi M
AD  - Department of Urology, Faculty of Medicine, Oita University, Yufu City, Japan.
FAU - Daa, Tsutomu
AU  - Daa T
AD  - Department of Diagnostic Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
FAU - Matsuura, Keiko
AU  - Matsuura K
AD  - Department of Biomedicine, Faculty of Medicine, Oita University, Yufu City, 
      Japan.
FAU - Shin, Toshitaka
AU  - Shin T
AD  - Department of Urology, Faculty of Medicine, Oita University, Yufu City, Japan.
FAU - Mimata, Hiromitsu
AU  - Mimata H
AD  - Department of Urology, Faculty of Medicine, Oita University, Yufu City, Japan.
FAU - Moriyama, Masatsugu
AU  - Moriyama M
AD  - Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu 
      City, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200320
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (MIRN210 microRNA, human)
RN  - 0 (MIRN210 microRNA, mouse)
RN  - 0 (MicroRNAs)
SB  - IM
MH  - Animals
MH  - Carcinoma, Renal Cell/*genetics
MH  - Energy Metabolism/genetics
MH  - Humans
MH  - Kidney Neoplasms/genetics/pathology
MH  - Kidney Tubules, Proximal/pathology
MH  - Mice, Transgenic
MH  - MicroRNAs/*genetics
MH  - Mitochondria/genetics/*metabolism
MH  - Oxidative Phosphorylation
OTO - NOTNLM
OT  - ISCU
OT  - NDUFA4
OT  - clear cell renal cell carcinoma (ccRCC)
OT  - metabolome
OT  - miR-210
OT  - mitochondrial alteration
OT  - transgenic mouse
EDAT- 2020/02/20 06:00
MHDA- 2020/09/18 06:00
CRDT- 2020/02/20 06:00
PHST- 2019/09/03 00:00 [received]
PHST- 2019/12/21 00:00 [revised]
PHST- 2020/02/10 00:00 [accepted]
PHST- 2020/02/20 06:00 [pubmed]
PHST- 2020/09/18 06:00 [medline]
PHST- 2020/02/20 06:00 [entrez]
AID - 10.1002/path.5394 [doi]
PST - ppublish
SO  - J Pathol. 2020 May;251(1):12-25. doi: 10.1002/path.5394. Epub 2020 Mar 20.