OXPHOS diseases

In view of the various clinical presentations possibly associated with OXPHOS diseases, it is becoming increasingly important for clinicians to recognize at least the syndromic presentations that are strongly suggestive of a mitochondrial disorder. In addition, however, any unexplained combination of neuromuscular and/or... 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

Deficiencies of electron transport In cells, complete transfer of electrons from NADH and FAD(2H) through the chain to O2 is necessary for ATP generation. Impaired transfer through any complex can have pathologic consequences. Fatigue can result from iron-defeciency anemia, which decreases Fe for Fe-S centers and cytochromes Cytochrome Cj oxidase, which contains the O2 binding site, is inhibited by cyanide Mitochondrial DNA (mtDNA), which is maternally inherited, encodes some of the subunits of the electron transport chain complexes and ATP synthase. Oxphos diseases are caused by mutations in nuclear DNA or mtDNA that decrease mitochondrial capacity for oxidative phosphorylation. 

Clinical diseases involving components of oxidative phosphorylation (referred to as OXPHOS diseases) are among the most commonly encountered degenerative diseases. The clinical pathology may be caused by gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encode proteins required for normal oxidative phosphorylation. 

Table 21.1 Examples of OXPHOS Diseases Arising from mtDNA Mutations...

Which of the following would be expected for a patient with an OXPHOS disease ... 

A number of other problems that interfere either with the electron transport chain or pyruvate oxidation in the TCA cycle result in lactic acidemia (see Fig.22.15). For example, OXPHOS diseases (inherited deficiencies in subunits of complexes in the electron transport chain, such as MERFF) increase the NADH/NAD ratio and... 

Ischemia/reperfusion injury following stroke Oxphos diseases (Mitochondrial DNA disorders) Multiple sclerosis Parkinson s disease... 

Central and/or peripheral nervous system involvement is one of the most frequent features, often resulting in the neonatal period in drowsiness, poor sucking, severe hypotonia, abnormal movements, seizures, respiratory distress, and fatal keto-acidotic coma with lactic acidosis [3]. To these severe conditions echo late-onset diseases now frequently attributed to or associated with mitochondrial OXPHOS defects, such as Alzheimer s or Parkinsons disease [10]. Major neurological symptoms, in variable combinations, involve trunk hypotonia, cranial nerve and brainstem involvement (with abnormal eye movements, ophthalmoplegia, recurrent apneas), cerebellar ataxia, myoclonia, seizures, pyramidal syndrome, peripheral neuropathy, poliodystrophy, and leukodystrophy infections [27,28]. A diffuse impairment of the cerebral white matter (leukodystrophy) mostly results in motor disturbance with mental retardation and low incidence of seizures. 

Some OXPHOS disorders, including Luft disease, result from mutations in nuclear DNA. A second group arise from point mutations in mtDNA and a third group involve deletions, often very large, in mtDNA. Persons with these deletions survive because they have both mutated and normal mtDNA, a condition of heteroplasmy of mtDNA. As these persons age their disease may become more severe because they lose many normal mitochondria.d,e... 

V2. van den Heuvel, L., and Smeitink, J., The oxidative phosphorylation (OXPHOS) system Nuclear genes and human genetic diseases. BioEssays 23, 518-525 (2001). 

LHON is a disorder caused by OXPHOS deficiency. Although more than 27 mutations have been associated with this disease, mtDNA mutations G3460A, G11778A, and... 

Ischaemic hearts of 7 patients aged 48 to 63 years had increased mtDNA damage and OXPHOS gene expression, suggesting that mtDNA damage is associated with OXPHOS deficiency (Corral-Debrinski et al. 1991). Oxidative phosphorylation defects may also play a role in some other forms of cardiac disease as idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, brown atrophy and coronary aAerosclerosis. 

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