RETRACTED: Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease

Abstract

Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes. Its catalytic centers, however, are encoded exclusively by two mitochondrial genes, CO1 and CO2 (encoding CO subunits I and II, respectively). We searched these genes, as well as other mitochondrial genes, for mutations that might alter CO activity and cosegregate with AD. In the present study, specific missense mutations in the mitochondrial CO1 and CO2 genes but not the CO3 gene were found to segregate at a higher frequency with AD compared with other neurodegenerative or metabolic diseases. These mutations appear together in the same mitochondrial DNA molecule and define a unique mutant mitochondrial genome. Asymptomatic offspring of AD mothers had higher levels of these mutations than offspring of AD fathers, suggesting that these mutations can be maternally inherited. Cell lines expressing these mutant mitochondrial DNA molecules exhibited a specific decrease in CO activity and increased production of reactive oxygen species. We suggest that specific point mutations in the CO1 and CO2 genes cause the CO defect in AD. A CO defect may represent a primary etiologic event, directly participating in a cascade of events that results in AD.

St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response

“…57,58 There is evidence that mitochondrial DNA polymorphisms may increase the susceptibility to Alzheimer disease, indicating that mitochondrial function might be relevant to a psychiatric phenotype. [59][60][61] Repeated DNA sequences: long interspersed elements (LINE) Rat LINE3 (or L1Rn) was included among the few genes that were differentially regulated by chronic antidepressant treatment with both IMI and SJW. This gene belongs to a family of repetitive DNA elements, which is ubiquitous in mammals, namely the L1 family.…”

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

“…The same would apply for the decrease of COX activity due to mutations of mtDNA in sporadic Alzheimer's disease (36). Although oxygen tension is usually considered not to be rate-limiting for electron transfer, this is not any more true when nitric oxide competitively inhibits COX; it is therefore plausible that NO keeps the respiratory chain more reduced, thus stimulating ROS production.…”

The other, forgotten genome: mitochondrial DNA and mental disorders

“…Although several mtDNA mutations/polymorphisms, such as 5460A, 19 4336C, [20][21][22] and 3397G, 20 have been associated with Alzheimer's disease, these findings have not been replicated by later studies. [23][24][25][26][27][28] And although heteroplasmic mutations were found in platelets from patients with Alzheimer's disease, 29 this was later found to be an artifact produced by pseudogenes from the nuclear genome. [30][31][32] Although increased levels of deletion in brains postmortem were reported, again this was not confirmed in subsequent studies.…”