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Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs
stem-progenitor cell cycling in the small intestine and restricts excess fat
Fox RG, Magness S, Kujoth GC, Prolla TA, Maeda N
Nobuyo Maeda on 3/4/2015
American journal of physiology. Gastrointestinal and liver physiology
Volume : Pages
302 : G914 - G924
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
Lieberkühn 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.
Investigators with authorship
University of North Carolina
Neuropathy & Neurocognition
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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