The other, forgotten genome: mitochondrial DNA and mental disorders

Abstract

This paper summarizes recent research on mitochondrial DNA (mtDNA)-which might be described as the 'other, forgotten genome'. Recent studies suggest the possible pathophysiological significance of mtDNA in schizophrenia and neurodegenerative and mood disorders. Decreased activity of the mitochondrial electron transport chain has been implicated in both Parkinson's and Alzheimer's disease and while age-related accumulation of mtDNA deletions has been suggested as a possible cause, there is no concrete evidence that particular mtDNA polymorphisms are responsible. In schizophrenia, the activity and/or mRNA expression of complex IV are involved, but the direction of the alteration is not the same and there is no evidence linking schizophrenia with mtDNA. In bipolar disorder, there is some evidence of parent-of-origin effects and association with mtDNA polymorphisms but further investigation is needed to elucidate the role of mtDNA in mental disorders. Molecular Psychiatry (2001) 6, 625-633.

Comprehensive expression analysis of a rat depression model

“…49,50 Evidence, including that of decreased ATP in frontal lobes detected in depressive patients, 51 has generated speculation about the role of mitochondrial dysfunction in depression. 52,53 NADH dehydrogenase is located on human chromosome 18 at p11.31-p11.2, a susceptibility region for affective disorder and schizophrenia. 3,54,55 These data suggest a possible link between mitochondrial NADH dehydrogenase and neuropsychiatric illnesses, including depression.…”

“…Among the genes coding for metabolic enzymes, the F1-ATPase epsilon subunit and 24-kDa subunit of mitochondrial NADH dehydrogenase are both localized to the mitochondria, further suggesting an important role for mitochondrial function in depression. 53 The second and third components in the FC did not further subdivide the experimental groups (supplementary figure S1). However, based on the data including the second component of PCA in the FC (supplementary Table S5), we speculate that genes responsible for neuronal growth and structure including Limk1 could be key factors in depression/stress-related pathology.…”

Mitochondrial involvement in psychiatric disorders

“…MtDNA is more susceptible to somatic deletions than nuclear DNA because mtDNA is not protected by histones and also has a poor DNA repair system. Thus mtDNA has been suggested as a potential 'weak point' of the genome (2,24). Examples of clinical syndromes related to mtDNA mutations include Leber hereditary optic neuropathy (LHON), which is associated with a number of ND1 (see list of abbreviations) gene mutations (25), and myopathy and diabetes mellitus which are associated with point mutations in mitochondrial tRNA (26).…”

“…The remaining subunits of the electron transport chain (see Figure 1) are encoded in the nuclear genome, which is physically separate from the cytoplasmically located mitochondrial genome. Each cell contains multiple mitochondria, and there are multiple copies of mtDNA in each mitochondrion (2). Muscle, brain, and liver often contain the highest number of mitochondria due to high energy utilization.…”

New variants in the mitochondrial genomes of schizophrenic patients

“…To test this hypothesis, we fixed three objectives: (1) to sequence the entire mitochondrial genome of patients with an apparent maternal transmission to find cytoplasmic-inherited mutations; (2) to test the presence of these mutations in a control population; and (3) to estimate, by bioinformatic methods, the possibility that these mutations could affect the structure or both the structure and function of proteins.…”