PMID- 32289346
OWN - NLM
STAT- MEDLINE
DCOM- 20200803
LR  - 20200803
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Linking)
VI  - 107
DP  - 2020 Jun
TI  - PINK1-PRKN mitophagy suppression by mangiferin promotes a brown-fat-phenotype via 
      PKA-p38 MAPK signalling in murine C3H10T1/2 mesenchymal stem cells.
PG  - 154228
LID - S0026-0495(20)30092-5 [pii]
LID - 10.1016/j.metabol.2020.154228 [doi]
AB  - OBJECTIVE: Mangiferin (MF), a xanthonoid derived from Mangifera indica, has shown 
      therapeutic effects on various human diseases including cancer, diabetes, and 
      obesity. Nonetheless, the influence of MF on non-shivering thermogenesis and its 
      underlying mechanism in browning remains unclear. Here, our aim was to 
      investigate the effects of MF on browning and its molecular mechanisms in murine 
      C3H10T1/2 mesenchymal stem cells (MSCs). MATERIALS/METHODS: To determine the 
      function of MF on browning, murine C3H10T1/2 MSCs were treated with MF in an 
      adipogenic differentiation cocktail and the thermogenic and correlated metabolic 
      responses were assessed using MF-mediated signalling. Human adipose-derived MSCs 
      were differentiated and treated with MF to confirm its role in thermogenic 
      induction. RESULTS: MF treatment induced the expression of a brown-fat signature, 
      UCP1, and reduced triglyceride (TG) in C3H10T1/2 MSCs. MF also induced the 
      expression of major thermogenesis regulators: PGC1alpha, PRDM16, and PPARgamma and 
      up-regulated the expression of beiging markers CD137, HSPB7, TBX1, and COX2 in 
      both murine C3H10T1/2 MSCs and human adipose-derived mesenchymal stem cells 
      (hADMSC). We also observed that MF treatment increased the mitochondrial DNA and 
      improved mitochondrial homeostasis by regulating mitofission-fusion plasticity 
      via suppressing PINK1-PRKN-mediated mitophagy. Furthermore, MF treatment improved 
      mitochondrial respiratory function by increasing mitochondrial oxygen consumption 
      and expression of oxidative-phosphorylation (OXPHOS)-related proteins. 
      Chemical-inhibition and gene knockdown experiments revealed that beta3-AR-dependent 
      PKA-p38 MAPK-CREB signalling is crucial for MF-mediated brown-fat formation via 
      suppression of mitophagy in C3H10T1/2 MSCs. CONCLUSIONS: MF promotes the brown 
      adipocyte phenotype by suppressing mitophagy, which is regulated by 
      PKA-p38MAPK-CREB signalling in C3H10T1/2 MSCs. Thus, we propose that MF may be a 
      good browning inducer that can ameliorate obesity.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Rahman, Md Shamim
AU  - Rahman MS
AD  - Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, 
      Cheonan, Chung-nam 31151, South Korea; Department of Microbiology, College of 
      Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea.
FAU - Kim, Yong-Sik
AU  - Kim YS
AD  - Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, 
      Cheonan, Chung-nam 31151, South Korea; Department of Microbiology, College of 
      Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, South Korea. 
      Electronic address: yongsikkim@sch.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200411
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (Xanthones)
RN  - 1M84LD0UMD (mangiferin)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (parkin protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (PTEN-induced putative kinase)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Adipocytes, Brown/drug effects
MH  - Adipose Tissue, Brown/*drug effects
MH  - Animals
MH  - Cell Differentiation/drug effects
MH  - Cyclic AMP-Dependent Protein Kinases/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mesenchymal Stem Cells/drug effects
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mitochondria/drug effects/metabolism
MH  - Mitophagy/*drug effects/*genetics
MH  - Oxidative Phosphorylation/drug effects
MH  - Oxygen Consumption/drug effects
MH  - Protein Kinases/drug effects/*genetics
MH  - Thermogenesis/drug effects/genetics
MH  - Ubiquitin-Protein Ligases/drug effects/*genetics
MH  - Xanthones/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/drug effects
OTO - NOTNLM
OT  - C3H10T1/2
OT  - Mangiferin
OT  - Mitochondrial biogenesis
OT  - PINK1-PRKN mitophagy
OT  - PKA-p38 MAPK-CREB
OT  - UCP1
COIS- Declaration of competing interest The authors declare that they have no conflicts 
      of interest.
EDAT- 2020/04/15 06:00
MHDA- 2020/08/04 06:00
CRDT- 2020/04/15 06:00
PHST- 2019/11/29 00:00 [received]
PHST- 2020/03/20 00:00 [revised]
PHST- 2020/04/07 00:00 [accepted]
PHST- 2020/04/15 06:00 [pubmed]
PHST- 2020/08/04 06:00 [medline]
PHST- 2020/04/15 06:00 [entrez]
AID - S0026-0495(20)30092-5 [pii]
AID - 10.1016/j.metabol.2020.154228 [doi]
PST - ppublish
SO  - Metabolism. 2020 Jun;107:154228. doi: 10.1016/j.metabol.2020.154228. Epub 2020 
      Apr 11.