Mitochondrial DNA mutations in human colonic crypt stem cells

Taylor, Robert W.; Barron, Martin J.; Borthwick, Gillian M.; Gospel, Amy; Chinnery, Patrick F.; Samuels, David C.; Taylor, Geoffrey A.; Plusa, S. M.; Needham, Stephanie; Greaves, Laura C.; Kirkwood, Thomas B. L.; Turnbull, Douglass M.

doi:10.1172/jci200319435

Cited by 149 publications

(183 citation statements)

References 45 publications

Supporting

Mentioning

174

Contrasting

Order By: Relevance

“…This may be due to differences in respiratory demand, permitting the mutation to accumulate, or at the level of selection. We have recently shown that human colonic crypt cells, another epithelial cell, can accumulate pathogenic mtDNA mutations to very high levels, 18 a phenomenon that we believe can be explained by virtue of these cells being short lived, and without significant selection against harmful mutations, they accumulate. Interestingly, a similar observation has also been made in hair follicles from patients with the 3243A4G mutation.…”

Section: Discussionmentioning

confidence: 93%

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

et al. 2004

View full text Add to dashboard Cite

The 3243A4G mutation is one of the most frequently observed mutations of mitochondrial DNA (mtDNA), and is associated with numerous clinical presentations including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), progressive external ophthalmoplegia (PEO) and diabetes and deafness. The routine diagnosis of the 3243A4G mutation in blood is difficult as mutation levels are known to decrease in this tissue over time, while in some patients it may be absent. We have directly compared the levels of the 3243A4G mutation in skeletal muscle, blood and urinary epithelial cells in 18 patients and observed a striking correlation between the mutation load in postmitotic muscle and urinary epithelium, a mitotic tissue. These data strongly support the use of urinary epithelial cells as the tissue of choice in the noninvasive diagnosis of the 3243A4G mutation.

show abstract

Section: Discussionmentioning

confidence: 93%

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

et al. 2004

View full text Add to dashboard Cite

show abstract

“…This phenomenon has been interpreted as a consequence of increased replication (clonal expansion) of defective mitochondria, presumably due to a replicative advantage of mutated mtDNA over normal mtDNA [57]. This possibility is supported by the occurrence of homoplasmic mtDNA mutations in neoplastic [65] and intestinal epithelial cells [66]. These cells are actively proliferating and, thus, cannot selectively accumulate mutated mitochondria, due to a decreased rate of elimination, as was suggested by de Grey in his survival of the slowest (SOS) hypothesis for postmitotic cells [67].…”

Section: Mechanisms Of Mitochondrial Damagementioning

confidence: 98%

Autophagy, organelles and ageing

Terman

Gustafsson

Brunk

2007

The Journal of Pathology

263

210

View full text Add to dashboard Cite

As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy and other degradative systems, long-lived postmitotic cells, such as cardiac myocytes, neurons and retinal pigment epithelial cells, progressively accumulate biological 'garbage' ('waste' materials). The latter include lipofuscin (a non-degradable intralysosomal polymeric substance), defective mitochondria and other organelles, and aberrant proteins, often forming aggregates (aggresomes). An interaction between senescent lipofuscin-loaded lysosomes and mitochondria seems to play a pivotal role in the progress of cellular ageing. Lipofuscin deposition hampers autophagic mitochondrial turnover, promoting the accumulation of senescent mitochondria, which are deficient in ATP production but produce increased amounts of reactive oxygen species. Increased oxidative stress, in turn, further enhances damage to both mitochondria and lysosomes, thus diminishing adaptability, triggering mitochondrial and lysosomal pro-apoptotic pathways, and culminating in cell death.

show abstract

“…In some cells, there is a high level of mutation involving the mitochondrial cytochrome c oxidase genes and associated with cytochrome c oxidase deficiency. We have shown that these cells clonally expand to occupy first part and then the whole crypt (also known as monoclonal conversion) (10), where the crypt becomes entirely colonized by mutated cells. Such conversion has previously been shown in mice that have DNA mutations in nuclear housekeeping genes such as G6PD and metallothionein induced by ethylnitrosourea (11,12).…”

mentioning

confidence: 99%

Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission

Greaves

Preston

Tadrous

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

273

280

View full text Add to dashboard Cite

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 >2.48 ؋ 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.fission ͉ mitochondria

show abstract

Mitochondrial DNA mutations in human colonic crypt stem cells

Abstract: contributed equally to this work. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: mitochondrial DNA (mtDNA); ribosomal RNA (rRNA); transfer RNA (tRNA); succinate dehydrogenase (SDH).

Cited by 149 publications

References 45 publications

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

Autophagy, organelles and ageing

Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission

Contact Info

Product

Resources

About