Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission.
The understanding of the fixation of mutations within human tissues and their subsequent clonal expansion is a considerable problem, of which little is known. We have previously shown that nononcogenic mutations in the mitochondrial genome occur in one of a number of morphologically normal colonic crypt stem cells, the progeny of which later occupy the whole crypt. We propose that these wholly mutated crypts then clonally expand by crypt fission, where each crypt divides into two mutated daughter crypts. Here we show that (i) mutated crypts in the process of fission share the same mutated mitochondrial genotype not present in neighboring cytochrome c oxidase-positive crypts (the odds of this being a random event are >or=2.48 x 10(9):1); (ii) neighboring mutated crypts have the same genotype, which is different from adjacent cytochrome c oxidase-positive crypts; (iii) mutated crypts are clustered together throughout the colon; and (iv) patches of cytochrome c oxidase-deficient crypts increase in size with age. We thus demonstrate definitively that crypt fission is the mechanism by which mutations spread in the normal human colon. This has important implications for the biology of the normal adult human colon and possibly for the growth and spread of colorectal neoplasms.
Greaves
Laura C
LC
Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom.
Preston
Sean L
SL
Tadrous
Paul J
PJ
Taylor
Robert W
RW
Barron
Martin J
MJ
Oukrif
Dahmane
D
Leedham
Simon J
SJ
Deheragoda
Maesha
M
Sasieni
Peter
P
Novelli
Marco R
MR
Jankowski
Janusz A Z
JA
Turnbull
Douglass M
DM
Wright
Nicholas A
NA
McDonald
Stuart A C
SA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division / Q000235:genetics; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D002999:Clone Cells; D003106:Colon / Q000166:cytology* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D004272:DNA, Mitochondrial