Geoffrey A. Taylor

Bio: Geoffrey A. Taylor is an academic researcher from Newcastle University. The author has contributed to research in topics: Mitochondrial DNA & Mutation. The author has an hindex of 26, co-authored 35 publications receiving 3368 citations. Previous affiliations of Geoffrey A. Taylor include University of Newcastle.

High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease.

Abstract: Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.

Mitochondrial DNA mutations in human colonic crypt stem cells

Abstract: The mitochondrial genome encodes 13 essential subunits of the respiratory chain and has remarkable genetics based on uniparental inheritance. Within human populations, the mitochondrial genome has a high rate of sequence divergence with multiple polymorphic variants and thus has played a major role in examining the evolutionary history of our species. In recent years it has also become apparent that pathogenic mitochondrial DNA (mtDNA) mutations play an important role in neurological and other diseases. Patients harbor many different mtDNA mutations, some of which are mtDNA mutations, some of which are inherited, but others that seem to be sporadic. It has also been suggested that mtDNA mutations play a role in aging and cancer, but the evidence for a causative role in these conditions is less clear. The accumulated data would suggest, however, that mtDNA mutations occur on a frequent basis. In this article we describe a new phenomenon: the accumulation of mtDNA mutations in human colonic crypt stem cells that result in a significant biochemical defect in their progeny. These studies have important consequences not only for understanding of the finding of mtDNA mutations in aging tissues and tumors, but also for determining the frequency of mtDNA mutations within a cell.

The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations

Abstract: Studies of single cells have previously shown intracellular clonal expansion of mitochondrial DNA (mtDNA) mutations to levels that can cause a focal cytochrome c oxidase (COX) defect. Whilst techniques are available to study mtDNA rearrangements at the level of the single cell, recent interest has focused on the possible role of somatic mtDNA point mutations in ageing, neurodegenerative disease and cancer. We have therefore developed a method that permits the reliable determination of the entire mtDNA sequence from single cells without amplifying contaminating, nuclear-embedded pseudogenes. Sequencing and PCR–RFLP analyses of individual COX-negative muscle fibres from a patient with a previously described heteroplasmic COX II (T7587C) mutation indicate that mutant loads as low as 30% can be reliably detected by sequencing. This technique will be particularly useful in identifying the mtDNA mutational spectra in age-related COX-negative cells and will increase our understanding of the pathogenetic mechanisms by which they occur.

Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing.

Abstract: Age-related decline in the integrity of mitochondria is an important contributor to the human ageing process. In a number of ageing stem cell populations, this decline in mitochondrial function is due to clonal expansion of individual mitochondrial DNA (mtDNA) point mutations within single cells. However the dynamics of this process and when these mtDNA mutations occur initially are poorly understood. Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques (Random Mutation Capture, Next Generation Sequencing and mitochondrial enzyme histochemistry), and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (<20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

Abstract: Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.

Mechanisms of mitophagy

Abstract: Mitophagy is the selective elimination of mitochondria through autophagy Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease

PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.

Abstract: Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.