) within four tissue sections. The cells have been stained by
immunohistochemistry to show a brown-orange color if the cells produce the
mitochondrial protein cytochrome c oxidase subunit I (CCOI, synonym for MT-COI), and the
nuclei of the cells (located at the outer edges of the cells lining the walls of the crypts) are stained blue-gray with
haematoxylin. Panels A, B were cut across the long axes of the crypts and panels C, D were cut parallel to the long axes of the crypts. In panel A the bar shows 100 μm and allows an estimate of the frequency of crypts in the colonic epithelium. Panel B includes three crypts in cross-section, each with one segment deficient for MT-COI expression and at least one crypt, on the right side, undergoing fission into two crypts. Panel C shows, on the left side, a crypt fissioning into two crypts. Panel D shows typical small clusters of two and three MT-COI deficient crypts (the bar shows 50 μm). The images were made from original photomicrographs, but panels A, B and D were also included in an article and illustrations were published with Creative Commons Attribution-Noncommercial License allowing re-use. The MT-COI protein, also known as CCOI, is usually expressed at a high level in the
cytoplasm of
colonic crypts of the human
large intestine (colon). However, MT-COI is frequently lost in colonic crypts with age in humans and is also often absent in field defects that give rise to colon cancers as well as in portions of colon cancers. showed that deficiencies of MT-COI in colonic crypts are due to mutations in the MT-COI gene. As seen in panel B, a portion of the stem cells of three crypts appear to have a mutation in MT-COI, so that 40% to 50% of the cells arising from those stem cells form a white segment in the cross-cut area. In humans, the percent of colonic crypts deficient for MT-COI is less than 1% before age 40, but then increases linearly with age. Based on these measurements, crypts have between 1725 and 2530 cells. Another report gave a range of 1500 to 4900 cells per colonic crypt. The occurrence of frequent crypts with almost complete loss of MT-COI in their 1700 to 5,000 cells suggests a process of natural selection. However, it has also been shown that a deficiency throughout a particular crypt due to an initial mitochondrial DNA mutation may occasionally occur through a stochastic process. Nevertheless, the frequent occurrence of MT-COI deficiency in many crypts within a colon epithelium indicates that absence of MT-COI likely provides a selective advantage. MT-COI is coded for by the
mitochondrial chromosome. There are multiple copies of the chromosome in most mitochondria, usually between 2 and 6 per mitochondrion. If a mutation occurs in MT-COI in one chromosome of a mitochondrion, there may be random segregation of the chromosomes during
mitochondrial fission to generate new mitochondria. This can give rise to a mitochondrion with primarily or solely MT-COI-mutated chromosomes. A mitochondrion with largely MT-COI-mutated chromosomes would need to have a positive
selection bias in order to frequently become the main type of mitochondrion in a cell (a cell with MT-COI-deficient
homoplasmy). There are about 100 to 700 mitochondria per cell, depending on cell type. and in mice is about 2 days. In humans it is likely that the half life of mitochondria is also a matter of days to weeks. A stem cell at the base of a colonic crypt that was largely MT-COI-deficient may compete with the other 4 or 5 stem cells to take over the stem cell niche. If this occurs, then the colonic crypt would be deficient in MT-COI in all 1700 to 5,000 cells, as is indicated for some crypts in panels A, B and D of the image. Crypts of the colon can reproduce by fission, as seen in panel C, where a crypt is fissioning to form two crypts, and in panel B where at least one crypt appears to be fissioning. Most crypts deficient in MT-COI are in clusters of crypts (clones of crypts) with two or more MT-COI-deficient crypts adjacent to each other (see panel D). These two factors may contribute to the frequent occurrence of MT-COI-deficient colonic crypts with age or during carcinogenesis in the human colon. == Interactions ==