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/jci19435

Cited by 469 publications

(415 citation statements)

References 45 publications

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“…Notwithstanding this caveat, the detection of mutant mtDNAs correlates well with cytochrome oxidase negative fibres, demonstrating that they are sufficiently abundant to cause loss of mitochondrial function. Moreover, different cell types and tissues clearly carry different types of mutant mtDNA, not only rearrangements, for which estimating the mutant load is straightforward [4,12,13].…”

Section: Hitch-hiking Deletions Of Mitochondrial Dnamentioning

confidence: 99%

“…However, to what extent a 'vicious cycle' of defective mtDNA, impaired mitochondrial respiration with increased oxygen radical formation, followed by further DNA mutation, contributes to loss of mitochondrial function is debated, as is the role of mitophagy in clearing deleterious mtDNAs [62,63]. Neither appears wholly satisfactory, as a vicious cycle cannot explain clonal expansion of specific mutant variants [4,12,13], and mitophagy clearly cannot meet the challenge of specifically disposing of disease-causing mutant mtDNAs, or again clonal expansion during ageing, although one can of course posit that it is an age-related decline in mitophagy that accounts for the latter phenomenon.…”

Section: Alternative Selection Mechanisms For Pathological Variants Amentioning

confidence: 99%

“…This distinction is recapitulated during ageing where deletions accumulate in post-mitotic tissues such as muscle, heart and brain, whereas it is point mutations that accumulate with age in dividing somatic cells (e.g. colonic crypts) [4]. These findings suggest deletions of mtDNA compromise cellular proliferation to some degree, whereas those point mutations that accumulate in dividing cells clearly cannot restrict the host cell's growth rate to any great extent (although some functional changes have been described) [5].…”

Section: Introductionmentioning

confidence: 99%

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The road to rack and ruin: selecting deleterious mitochondrial DNA variants

Holt¹,

Speijer

Kirkwood

2014

Phil. Trans. R. Soc. B

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Mitochondria constitute the major energy-producing compartment of the eukaryotic cell. These organelles contain many molecules of DNA that contribute only a handful of proteins required for energy production. Mutations in the DNA of mitochondria were identified as a cause of human disease a quarter of a century ago, and they have subsequently been implicated in ageing. The process whereby deleterious variants come to dominate a cell, tissue or human is the subject of debate. It is likely to involve multiple, often competing, factors, as selection pressures on mitochondrial DNA can be both indirect and intermittent, and are subjected to rapid change. Here, we assess the different models and the prospects for preventing the accumulation of deleterious mitochondrial DNA variants with time.

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Section: Hitch-hiking Deletions Of Mitochondrial Dnamentioning

confidence: 99%

Section: Alternative Selection Mechanisms For Pathological Variants Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The road to rack and ruin: selecting deleterious mitochondrial DNA variants

Holt¹,

Speijer

Kirkwood

2014

Phil. Trans. R. Soc. B

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“…Mitochondrial DNA damage increases in aging rodents (Hamilton et al ., 2001; Genova et al ., 2004; Hagen et al ., 2004) and humans (Taylor et al ., 2003), and these increases in mutation can lead to reduced flow through the electron transport chain during aging (Wanagat et al ., 2001; Hagen et al ., 2004; Short et al ., 2005; reviewed in Golden & Melov, 2001; Ikeda et al ., 2014). …”

Section: Testing Predictions Of This Modelmentioning

confidence: 99%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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“…By contrast, the second theory states that a single cell can dominate the stem cell pool and hence the entire crypt. Recently, mitochondrial DNA mutations have been used to track the progress of different populations within the crypt [44][45][46]. The data suggest that, over time, a single cell's progeny can dominate a crypt, via a process termed monoclonal conversion.…”

Section: Monoclonal Conversion In Cryptsmentioning

confidence: 99%

Chaste: A test-driven approach to software development for biological modelling

Pitt-Francis

Pathmanathan

Bernabéu

et al. 2009

Computer Physics Communications

215

181

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Chaste ('Cancer, heart and soft-tissue environment') is a software library and a set of test suites for computational simulations in the domain of biology. Current functionality has arisen from modelling in the fields of cancer, cardiac physiology and soft-tissue mechanics. It is released under the LGPL 2.1 licence. Chaste has been developed using agile programming methods. The project began in 2005 when it was reasoned that the modelling of a variety of physiological phenomena required both a generic mathematical modelling framework, and a generic computational/simulation framework. The Chaste project evolved from the Integrative Biology (IB) e-Science Project, an inter-institutional project aimed at developing a suitable IT infrastructure to support physiome-level computational modelling, with a primary focus on cardiac and cancer modelling. Program summaryProgram title: Chaste Catalogue identifier: AEFD_v1_0 Program summary URL:

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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 469 publications

References 45 publications

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

The road to rack and ruin: selecting deleterious mitochondrial DNA variants

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Chaste: A test-driven approach to software development for biological modelling

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