PMID- 31685549
OWN - NLM
STAT- MEDLINE
DCOM- 20200408
LR  - 20220129
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 40
IP  - 2
DP  - 2020 Jan 3
TI  - Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine 
      Sparing in the Mitochondria.
LID - 10.1128/MCB.00212-19 [doi]
LID - e00212-19
AB  - Anabolic and catabolic signaling mediated via mTOR and AMPK (AMP-activated 
      kinase) have to be intrinsically coupled to mitochondrial functions for 
      maintaining homeostasis and mitigate cellular/organismal stress. Although 
      glutamine is known to activate mTOR, whether and how differential mitochondrial 
      utilization of glutamine impinges on mTOR signaling has been less explored. 
      Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is 
      known to inhibit catabolic signaling/pathways through the 
      AMPK-PGC1alpha/SIRT1-peroxisome proliferator-activated receptor alpha (PPARalpha) axis and 
      negatively regulate glutamine metabolism via the tricarboxylic acid cycle. 
      However, physiological significance of SIRT4 functions during a fed state is 
      still unknown. Here, we establish SIRT4 as key anabolic factor that activates 
      TORC1 signaling and regulates lipogenesis, autophagy, and cell proliferation. 
      Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic 
      conversion of glutamine to alpha-ketoglutarate potentiates TORC1. Interestingly, we 
      also show that mitochondrial glutamine sparing or utilization is critical for 
      differentially regulating TORC1 under fed and fasted conditions. Moreover, we 
      conclusively show that differential expression of SIRT4 during fed and fasted 
      states is vital for coupling mitochondrial energetics and glutamine utilization 
      with anabolic pathways. These significant findings also illustrate that SIRT4 
      integrates nutrient inputs with mitochondrial retrograde signals to maintain a 
      balance between anabolic and catabolic pathways.
CI  - Copyright (c) 2020 American Society for Microbiology.
FAU - Shaw, Eisha
AU  - Shaw E
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India.
FAU - Talwadekar, Manasi
AU  - Talwadekar M
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India.
FAU - Rashida, Zeenat
AU  - Rashida Z
AD  - Regulation of Cell Fate, Institute of Stem Cell Science and Regenerative Medicine 
      (InStem), Bangalore, India.
FAU - Mohan, Nitya
AU  - Mohan N
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India.
FAU - Acharya, Aishwarya
AU  - Acharya A
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India.
FAU - Khatri, Subhash
AU  - Khatri S
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India.
FAU - Laxman, Sunil
AU  - Laxman S
AD  - Regulation of Cell Fate, Institute of Stem Cell Science and Regenerative Medicine 
      (InStem), Bangalore, India.
FAU - Kolthur-Seetharam, Ullas
AU  - Kolthur-Seetharam U
AD  - Department of Biological Sciences, Tata Institute of Fundamental Research, 
      Colaba, Mumbai, India ullas@tifr.res.in.
LA  - eng
GR  - IA/I/14/2/501523/WTDBT_/DBT-Wellcome Trust India Alliance/India
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200103
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Mitochondrial Proteins)
RN  - 0RH81L854J (Glutamine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 3.5.1.- (SIRT4 protein, human)
RN  - EC 3.5.1.- (SIRT4 protein, mouse)
RN  - EC 3.5.1.- (Sirtuins)
SB  - IM
MH  - Animals
MH  - Autophagy
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Glutamine/metabolism
MH  - HEK293 Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - Lipogenesis
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Mitochondria/*metabolism
MH  - Mitochondrial Proteins/*metabolism
MH  - *Signal Transduction
MH  - Sirtuins/*metabolism
PMC - PMC6944470
OTO - NOTNLM
OT  - AMPK
OT  - S6K
OT  - SIRT4
OT  - SREBP1c
OT  - TORC1
OT  - anaplerosis
OT  - autophagy
OT  - glutamate dehydrogenase
OT  - lipogenesis
OT  - mitochondria
EDAT- 2019/11/07 06:00
MHDA- 2020/04/09 06:00
PMCR- 2020/07/03
CRDT- 2019/11/06 06:00
PHST- 2019/05/10 00:00 [received]
PHST- 2019/10/28 00:00 [accepted]
PHST- 2019/11/07 06:00 [pubmed]
PHST- 2020/04/09 06:00 [medline]
PHST- 2019/11/06 06:00 [entrez]
PHST- 2020/07/03 00:00 [pmc-release]
AID - MCB.00212-19 [pii]
AID - 00212-19 [pii]
AID - 10.1128/MCB.00212-19 [doi]
PST - epublish
SO  - Mol Cell Biol. 2020 Jan 3;40(2):e00212-19. doi: 10.1128/MCB.00212-19. Print 2020 
      Jan 3.