I searched PubMed and Medline with the search terms “mitochondrial DNA”, “polymerase gamma”, “mitochondria”, “Parkinson's disease”, “mitochondrial biogenesis” “neurodegeneration”, “diabetes”, “Alzheimer's disease”, and “Huntington's disease” for articles published between January, 2005, and July, 2011. Papers were also identified from the references lists of relevant articles and through searches of my files. Only papers published in English or with abstracts in English were selected.
SeminarMitochondrial diseases
Introduction
Advances in genetics and cell biology have provided valuable insights into the function of mitochondria and into the contribution of defects of mitochondrial metabolism to human disease. Almost 200 different mutations of mitochondrial DNA (mtDNA) have been reported in human beings. This Seminar provides an update on the pathogenesis of diseases (particularly neurodegenerative disorders) associated with mitochondrial dysfunction, and reviews the emerging area of mitochondrial pharmacology. The appendix summarises the basic biology of mitochondria and disease.1, 2, 3 Other important areas of interest to mitochondrial biology and pathology that cannot be covered in detail here include neoplasia and anticancer therapies. The relation between neurodegeneration and cancer has been highlighted4 and the potential for somatic mutations of mtDNA to affect both the cell biology of neoplasia and the sensitivity or resistance of cells to chemotherapy has been noted.
Section snippets
Definition
Abnormalities of mitochondrial function that contribute or lead to human disease can derive from several sources. Mutations of mtDNA are a primary cause and can be due to inherited sequence changes in the mtDNA genome (eg, deletions, rearrangements, point mutations [table 1]), secondary to nuclear gene mutations causing, for example, mtDNA multiple deletions or depletion (table 2), or somatic—eg, as result of free-radical-mediated damage or faulty repair. Since the genome encodes 13 proteins of
Mitochondrial quality control
Mitochondria can divide (fission) or fuse, and these processes are important to mitochondrial transport. Fission-fusion is regulated by several signalling proteins, such as mitofusins 1 and 2, which mediate fusion of mitochondrial outer membranes, and optic atrophy protein 1, a dynamin-like GTPase involved in fusion of the inner membranes. Dynamin-1-like protein 1 and fission 1 homologue regulate mitochondrial fission.5
An important function of the fission-fusion process is to maintain the
mtDNA mutations and disease
The prevalence of mtDNA mutations is difficult to establish with accuracy, especially because of the high asymptomatic carrier rate. However, studies have shown a prevalence for specific mutations of 0·14–0·20%.21, 22 mtDNA mutations are associated with a very wide range of clinical expression (table 1). Manifestations of mtDNA mutations vary from oligosymptomatic states (eg, isolated sensorineural deafness or type 2 diabetes) to complex multisystem syndromes that might involve neurological,
Respiratory chain defects
The five protein complexes of the oxidative phosphorylation system can be rendered defective by any of the mtDNA mutations outlined in this Seminar, or by mutations of nuclear genes encoding oxidative phosphorylation proteins. Selective dysfunction of a complex can occur, but combinations of defects are more common (table 3). Pure complex I defects are seen as a result of mutations of mtDNA complex I genes, such as in Leber's hereditary optic neuropathy, or of nuclear complex I genes, which
Management of diseases with mtDNA mutations
Guidelines for the diagnosis of mtDNA diseases have been published.33 Early attempts to treat primary mitochondrial disorders used supplements, vitamins, substrates, or electron carriers—eg, coenzyme Q10.34, 35 However, many of these treatments were of little value and no randomised studies with a sufficiently large number of patients to provide a definitive result were done. Coenzyme Q is of clear benefit to patients with primary coenzyme Q10 deficiency, and creatine is useful in the treatment
Mitochondrial dysfunction and Parkinson's disease
Mitochondrial dysfunction in Parkinson's disease was first identified in 1989, and accumulating evidence suggests a primary role in pathogenesis.46, 47, 48 An early consideration was whether mtDNA mutations might account for a proportion of Parkinson's disease cases. However, no large-scale mtDNA rearrangements were recorded in brains of patients with Parkinson's disease,49 although more detailed analysis with laser capture of dopaminergic neurons from parkinsonian brains showed a greater
Mitochondrial dysfunction and Alzheimer's disease
Apart from age, important risk factors for Alzheimer's disease include apolipoprotein ɛ4 status and mutations of amyloid precursor protein or presenilin. Investigators of several studies have reported abnormalities of mitochondrial structure or function, or mtDNA defects in the brain or other tissues and cells of patients with Alzheimer's disease, but the presence and relevance of these findings have remained controversial, and the data derived have not always been reproducible.
However, new
Mitochondrial dysfunction and Huntington's disease
Huntington's disease is caused by a triplet repeat expansion in the huntingtin gene encoding an enlarged polyglutamine sequence in the mature protein. Mitochondrial defects have been described in patients with Huntington's disease in vivo, in affected brains post mortem, and in cell and animal models of the disease.85, 86, 87, 88
The mitochondrial defects in Huntington's disease are associated with abnormalities of calcium handling, increased susceptibility to calcium-induced opening of the
Other neurodegenerative diseases
Mitochondrial dysfunction has been identified in several other neurodegenerative diseases. Secondary abnormalities of mitochondrial morphology and function have been recorded in amyotrophic latereral sclerosis,98 whereas in other disorders the causative gene mutation involves a mitochondrial protein (table 4)—eg, Friedreich's ataxia99 and hereditary spastic paraplegia.100 Mutations in the MFN2 gene are a common cause of autosomal dominant Charcot-Marie-Tooth type 2 disease—an early-onset axonal
Mitochondrial dysfunction and visual failure
Mitochondrial dysfunction has been a topic of interest to ophthalmological practice since the identification of mtDNA mutations as a cause of Leber's hereditary optic neuropathy.105 OPA1 mutations are a cause of optic atrophy, and mtDNA mutations associated with encephalomyopathies can be associated with ophthalmoplegia or retinal pigmentation. Attention is now focused on the potential involvement of mitochondria in glaucoma. The cause of glaucoma is multifactorial; age and ocular pressure are
Mitochondrial dysfunction and diabetes mellitus
Diabetes mellitus is a recognised feature of many mitochondrial disorders. It can be the sole expression of mtDNA mutations, but is also frequently recorded as part of an encephalomyopathy (eg, MELAS), and is associated with Friedreich's ataxia and Huntington's disease. Mitochondria play a crucial part in glucose signalling for insulin release and mitochondrial defects impair this process, as in turn does persistent hyperglycaemia, leading to mitochondrial dysfunction and reduced insulin
Substrates, carriers, and antioxidants
The discovery of mitochondrial defects in several common neurodegenerative diseases provided the basis and sufficient numbers of patients to begin to assess applicability of compounds such as coenzyme Q10 and creatine to treat disorders of mitochondrial function.119 Coenzyme Q10 is an electron carrier and antioxidant. At a dose of 1200 mg per day, coenzyme Q10 seemed to slow progression in a pilot study in early Parkinson's disease,120 although other studies using similar bioavailable doses
Search strategy and selection criteria
Conflicts
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