Mitochondrial DNA 3644T-->C mutation associated with bipolar disorder.
Mitochondrial dysfunction associated with mutant mitochondrial DNA (mtDNA) has been suggested in bipolar disorder, and comorbidity with neurodegenerative diseases was often noted. We examined the entire sequence of mtDNA in six subjects with bipolar disorder having comorbid somatic symptoms suggestive of mitochondrial disorders and found several uncharacterized homoplasmic nonsynonymous nucleotide substitutions of mtDNA. Of these, 3644C was found in 5 of 199 patients with bipolar disorder but in none of 258 controls (p = 0.015). The association was significant in the extended samples [bipolar disorder, 9/630 (1.43%); controls, 1/734 (0.14%); p = 0.007]. On the other hand, only 5 of 25 family members with this mutation developed bipolar disorder, of which 4 patients with 3644C had comorbid physical symptoms. The 3644T-->C mutation converts amino acid 113, valine, to alanine in the NADH-ubiquinone dehydrogenase subunit I, a subunit of complex I, and 113 valine is well conserved from Drosophila to 61 mammalian species. Using transmitochondrial cybrids, 3644T-->C was shown to decrease mitochondrial membrane potential and complex I activity compared with haplogroup-matched controls. According to human mitochondrial genome polymorphism databases, 3644C was not found in centenarians but was found in 3% of patients with Alzheimer disease and 2% with Parkinson disease. The result of modest functional impairment caused by 3644T-->C suggests that this mutation could increase the risk for bipolar disorder.
Munakata
Kae
K
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Hirosawa 2-1, Wako, Saitama 351-0198, Japan.
Tanaka
Masashi
M
Mori
Kanako
K
Washizuka
Shinsuke
S
Yoneda
Makoto
M
Tajima
Osamu
O
Akiyama
Tsuyoshi
T
Nanko
Shinichiro
S
Kunugi
Hiroshi
H
Tadokoro
Kazuyuki
K
Ozaki
Norio
N
Inada
Toshiya
T
Sakamoto
Kaoru
K
Fukunaga
Takako
T
Iijima
Yoshimi
Y
Iwata
Nakao
N
Tatsumi
Masahiko
M
Yamada
Kazuo
K
Yoshikawa
Takeo
T
Kato
Tadafumi
T
D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I