Dissecting the mechanisms underlying the accumulation of mitochondrial DNA deletions in human skeletal muscle.

Large-scale mitochondrial DNA (mtDNA) deletions are an important cause of mitochondrial disease, while somatic mtDNA deletions cause focal respiratory chain deficiency associated with ageing and neurodegenerative disorders. As mtDNA deletions only cause cellular pathology at high levels of mtDNA heteroplasmy, an mtDNA deletion must accumulate to levels which can result in biochemical dysfunction-a process known as clonal expansion. A number of hypotheses have been proposed for clonal expansion of mtDNA deletions, including a replicative advantage for deleted mitochondrial genomes inferred by their smaller size--implying that the largest mtDNA deletions would also display a replicative advantage over smaller mtDNA deletions.

Late-onset respiratory failure due to TK2 mutations causing multiple mtDNA deletions.

Mutations in nuclear genes involved in the maintenance of mitochondrial DNA (mtDNA) are associated with an extensive spectrum of clinical phenotypes, manifesting as either mtDNA depletion syndromes or multiple mtDNA deletion disorders.(1.)

Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis.

Mitochondrial DNA deletions (∆-mtDNA) have been implicated in the pathogenesis of Alzheimer's disease (AD), multiple sclerosis (MS) and Parkinson's disease (PD), as well as ageing. Clonal expansion of ∆-mtDNA is the process by which a mutant mtDNA molecule increases to high levels within a single cell containing both wild-type and mutant mtDNA. Unlike in AD and PD, the diffuse inflammatory process in MS involves the choroid plexus, and mitochondria are exposed to reactive oxygen and nitrogen species over a prolonged period.

Relationship between mitochondria and α-synuclein: a study of single substantia nigra neurons.

Objective: To explore the relationship between α-synuclein pathology and mitochondrial respiratory chain protein levels within single substantia nigra neurons.

Design: We examined α-synuclein and mitochondrial protein expression in substantia nigra neurons of 8 patients with dementia with Lewy bodies, 5 patients with Parkinson disease, and 8 control subjects. Protein expression was determined using immunocytochemistry followed by densometric analysis.

Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia, increasing in prevalence with age. Most patients who develop AD have an unknown cause, but characteristic neuropathological features include the deposition of extracellular amyloid beta and of intraneuronal hyperphosphorylated tau protein. Researchers have previously implicated mitochondrial dysfunction in AD.

Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis.

Objective: Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system.

Repeats, longevity and the sources of mtDNA deletions: evidence from 'deletional spectra'.

Perfect direct repeats and, in particular, the prominent 13 bp repeat, are thought to cause mitochondrial DNA (mtDNA) deletions, which have been associated with the aging process. Accordingly, individuals lacking the 13 bp repeat are highly prevalent among centenarians and overall number of perfect repeats in mammalian mitochondrial genomes negatively correlates with species' longevity. However, detailed examination of the distribution of mtDNA deletions challenges a special role of the 13 bp repeat in generating mtDNA deletions.

Mitochondrial DNA and genetic disease.

From their very beginning to the present day, mitochondria have evolved to become a crucial organelle within the cell. The mitochondrial genome encodes only 37 genes, but its compact structure and minimal redundancy results in mutations on the mitochondrial genome being an important cause of genetic disease. In the present chapter we describe the up-to-date knowledge about mitochondrial DNA structure and function, and describe some of the consequences of defective function including disease and aging.

Older mothers are not at risk of having grandchildren with sporadic mtDNA deletions.

Purpose: Single large-scale mitochondrial DNA deletions account for a quarter of mitochondrial disease cases and occur sporadically with unknown risk factors. Mitochondrial DNA deletions accumulate with age in many tissues. Primordial germ cells, the precursors of oocytes are made by our grandmothers, therefore we wanted to determine whether age of maternal grandmother is a risk factor for sporadic mitochondrial DNA deletions.

Detection of mitochondrial DNA variation in human cells.

The ability to detect mitochondrial DNA (mtDNA) variation within human cells is important not only to identify mutations causing mtDNA disease, but also as mtDNA mutations are being increasingly described in many ageing tissues and in complex diseases such as diabetes, neurodegeneration and cancer. In this review, we discuss the main molecular genetic techniques that can be applied to study the two main types of mtDNA mutation: point mutations and large-scale mtDNA rearrangements. We then describe in detail protocols routinely used within our laboratory to analyse mtDNA mutations in individual human cells such as single muscle fibres and individual neurons to study the relationship between mtDNA mutation load and respiratory chain dysfunction.

Mitochondrial DNA defects and selective extraocular muscle involvement in CPEO.

PURPOSE. Chronic progressive external ophthalmoplegia (CPEO) is a prominent, and often the only, presentation among patients with mitochondrial diseases. The mechanisms underlying the preferential involvement of extraocular muscles (EOMs) in CPEO were explored in a comprehensive histologic and molecular genetic study, to define the extent of mitochondrial dysfunction in EOMs compared with that in skeletal muscle from the same patient.

The low abundance of clonally expanded mitochondrial DNA point mutations in aged substantia nigra neurons.

Clonally expanded mitochondrial DNA (mtDNA) deletions accumulate with age in human substantia nigra (SN) and high levels cause respiratory chain deficiency. In other human tissues, mtDNA point mutations clonally expand with age. Here, the abundance of mtDNA point mutations within single SN neurons from aged controls was investigated.

Mitochondrial DNA mutations in disease, aging, and neurodegeneration.

Patients with disorders from mutations in the mitochondrial genome have variable phenotypes, but common to many of these disorders are underlying changes in postmitotic cells, particularly neurons and muscle fibers. The mitochondrial dysfunction caused by these mutations has been shown to be associated with signs of apoptosis and to cause cell loss. Mutations of the mitochondrial genome have also been shown to accumulate with age and in common neurodegenerative diseases, such as Parkinson's disease.

Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions.

Mitochondrial dysfunction is a consistent finding in neurodegenerative disorders like Alzheimer's (AD) or Parkinson's disease (PD) but also in normal human brain aging. In addition to respiratory chain defects, damage to mitochondrial DNA (mtDNA) has been repeatedly reported in brains from AD and PD patients. Most studies though failed to detect biologically significant point mutation or deletion levels in brain homogenate.

Age related mitochondrial degenerative disorders in humans.

Disorders caused by mitochondrial respiratory chain deficiency due to mutations in mitochondrial DNA have varied phenotypes but many involve neurological features often associated with cell loss within specific brain regions. These disorders, along with the increasing evidence of decline in mitochondrial function with ageing, have raised speculation that primary changes in mitochondria could have an important role in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence supporting a role for mitochondria in common neurodegenerative diseases comes from studies with the toxin MPP+ and familial PD, which has been shown to involve proteins such as DJ-1 and Pink1 (both of which are predicted to have a role in mitochondrial function and oxidative stress).

What causes mitochondrial DNA deletions in human cells?

Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication.

Nature of mitochondrial DNA deletions in substantia nigra neurons.

Mitochondrial DNA (mtDNA) deletions have been investigated in a number of neurodegenerative diseases. This study aimed to investigate the characteristics of mtDNA deletions found in single substantia nigra neurons from three patient groups: controls, Parkinson disease patients, and a patient with Parkinsonism due to multiple mtDNA deletions. We have identified 89 deletions from these neurons and examined the breakpoint characteristics of them.

The ageing mitochondrial genome.

The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process.

Mitochondrial DNA mutations and aging.

Mitochondria have been hypothesized to play a role in both aging and neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. Many studies have shown the accumulation of mitochondrial DNA (mtDNA) mutations in post-mitotic tissues and more recent data have shown this also to be a feature of aging mitotic tissues. Much of this data has been correlative, until recently with the development of polymerase gamma deficient mice which accumulate high levels of mtDNA mutations and show a premature aging phenotype, that a more causative role has been proposed.

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

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.

The incidence of both tandem duplications and the common deletion in mtDNA from three distinct categories of sun-exposed human skin and in prolonged culture of fibroblasts.

The use of mtDNA damage as a biomarker of cumulative sunlight exposure in human skin is a relatively new field of research. Previous investigations have simply compared the frequency of occurrence of the mtDNA common deletion (CD), and to a much lesser extent that of tandem duplications (TDs), to distinguish between sun-protected and sun-exposed skin. This approach is limited because non-melanoma skin cancer is predominantly formed on body sites that are "usually" sun-exposed as opposed to sites that are "occasionally" sun-exposed and as such they differ in their cumulative UV exposure.

The use of a 3895 bp mitochondrial DNA deletion as a marker for sunlight exposure in human skin.

Previous work has examined the use of mitochondrial DNA (mtDNA) damage as a biomarker of cumulative sun exposure in human skin. These studies have simply compared mtDNA damage between sun-protected and sun exposed skin. This approach is limited because non-melanoma skin cancer (NMSC) is predominantly formed on body sites which are 'usually' sun exposed as opposed to sites which are 'occasionally' sun exposed and as such they differ in their cumulative ultraviolet (UV) exposure.