PMID- 22345551
OWN - NLM
STAT- MEDLINE
DCOM- 20120625
LR  - 20211021
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 302
IP  - 9
DP  - 2012 May 1
TI  - Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs 
      stem-progenitor cell cycling in the small intestine and restricts excess fat 
      absorption.
PG  - G914-24
LID - 10.1152/ajpgi.00402.2011 [doi]
AB  - Changes in intestinal absorption of nutrients are important aspects of the aging 
      process. To address this issue, we investigated the impact of accelerated 
      mitochondrial DNA mutations on the stem/progenitor cells in the crypts of 
      Lieberkuhn in mice homozygous for a mitochondrial DNA polymerase gamma mutation, 
      Polg(D257A), that exhibit accelerated aging phenotype. As early as 3-7 mo of age, 
      the small intestine was significantly enlarged in the PolgD257A mice. The crypts 
      of the PolgD257A mice contained 20% more cells than those of their wild-type 
      littermates and exhibited a 10-fold increase in cellular apoptosis primarily in 
      the stem/progenitor cell zones. Actively dividing cells were proportionally 
      increased, yet a significantly smaller proportion of cells was in the S phase of 
      the cell cycle. Stem cell-derived organoids from PolgD257A mice failed to develop 
      fully in culture and exhibited fewer crypt units, indicating an impact of the 
      mutation on the intestinal epithelial stem/progenitor cell maintenance. In 
      addition, epithelial cell migration along the crypt-villus axis was slowed and 
      less organized, and the ATP content in the villi was significantly reduced. On a 
      high-fat, high-carbohydrate diet, PolgD257A mice showed significantly restricted 
      absorption of excess lipids accompanied by an increase in fecal steatocrits. We 
      conclude that the PolgD257A mutation causes cell cycle dysregulation in the 
      crypts leading to the age-associated changes in the morphology of the small 
      intestine and contributes to the restricted absorption of dietary lipids.
FAU - Fox, Raymond G
AU  - Fox RG
AD  - Curriculum in Genetics and Molecular Biology, Department of Pathology and 
      Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 
      27599, USA.
FAU - Magness, Scott
AU  - Magness S
FAU - Kujoth, Gregory C
AU  - Kujoth GC
FAU - Prolla, Tomas A
AU  - Prolla TA
FAU - Maeda, Nobuyo
AU  - Maeda N
LA  - eng
GR  - HL-42630/HL/NHLBI NIH HHS/United States
GR  - HL-087946/HL/NHLBI NIH HHS/United States
GR  - R01 HL049277/HL/NHLBI NIH HHS/United States
GR  - T32-HL-69768/HL/NHLBI NIH HHS/United States
GR  - U01 HL087946/HL/NHLBI NIH HHS/United States
GR  - R01 HL042630/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120216
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Dietary Fats)
RN  - EC 2.7.7.7 (DNA Polymerase gamma)
RN  - EC 2.7.7.7 (DNA-Directed DNA Polymerase)
RN  - EC 2.7.7.7 (Polg protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Count
MH  - Cell Cycle/*genetics
MH  - DNA Polymerase gamma
MH  - DNA-Directed DNA Polymerase/*genetics
MH  - Dietary Fats/*metabolism
MH  - Intestinal Absorption/*genetics/physiology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Mutation/*genetics
MH  - RNA Editing/genetics
MH  - Stem Cells/*cytology/*physiology
PMC - PMC3362078
EDAT- 2012/02/22 06:00
MHDA- 2012/06/26 06:00
PMCR- 2013/05/01
CRDT- 2012/02/21 06:00
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/06/26 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - ajpgi.00402.2011 [pii]
AID - GI-00402-2011 [pii]
AID - 10.1152/ajpgi.00402.2011 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2012 May 1;302(9):G914-24. doi: 
      10.1152/ajpgi.00402.2011. Epub 2012 Feb 16.