title: Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption.
abstract: 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.
authors.affiliation: Curriculum in Genetics and Molecular Biology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Fox
authors.forename: Scott
authors.initials: S
authors.lastname: Magness
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Kujoth
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004041:Dietary Fats / Q000378:metabolism*; D007408:Intestinal Absorption / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D017393:RNA Editing / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse