New variants in the mitochondrial genomes of schizophrenic patients

Abstract

The impaired mitochondrial function hypothesis in schizophrenia is based on evidence of altered brain metabolism, morphology, biochemistry and gene expression. Mitochondria have their own genome, which is needed to synthesize some of the subunits of the respiratory chain enzymes. Mitochondrial DNA (mtDNA) is maternally inherited and we observed an excess of maternal transmission of schizophrenia in a set of parent -offspring affected pairs. We therefore hypothesized that mutations in the mtDNA may contribute to the complex genetic basis of schizophrenia. The entire mtDNA of six schizophrenic patients with an apparent maternal transmission of the disease was sequenced and compared to the reference sequence. We have identified 50 variants and among these six have not been previously reported. Three of them were missense variants: MTCO2 7750C4A, MTATP6 8857G4A and MTND4 12096T4A. These were maternally inherited because they were also present in the mtDNA of their respective schizophrenic mothers and none of them were found in 95 control individuals. The MTND4 12096T4A (Leu446His) is a heteroplasmic variant present in five of the six mother -offspring patient pairs that triggers a nonconservative substitution in the ND4 subunit of complex I. Sequence alignment of 110 ND4 peptides from all eukaryotic kingdoms shows that only hydrophobic amino acids are found in this position. Moreover, leucine was conserved or substituted by an isoleucine in all mammalian species. This indicates that the presence of histidine could affect complex I activity in patients with schizophrenia.

The mitochondrial genome and psychiatric illness

“…Four studies have sequenced the entire mitochondrial genome in patients with schizophrenia [Lindholm et al, 1997;Martorell et al, 2006;Bamne et al, 2008;Ueno et al, 2009]. The first sequenced two patients with schizophrenia and low complex IV activity in post-mortem brain, and two related patients with suspected maternal inheritance [Lindholm et al, 1997].…”

Mitochondrial involvement in psychiatric disorders

“…This is known as heteroplasmy (28). The six subjects with SZ had 50 variants compared to the revised Cambridge reference sequence (82). The variants did not accumulate in a specific region of the mtDNA genome.…”

Mitochondrial Proteomics: From Structure to Function

“…Together with this, mitochondrial energy metabolism might be disturbed by the antipsychotic drugs used (Modica-Napolitano et al, 2003). Various antipsychotic drugs have been available for treatment: chlorpromazine (CPZ), was in the first generation and presents serious side-effects (Freedman, 2003); clozapine (CLZ), the first atypical antipsychotic drug to present more antipsychotic effects without the adverse mobility effects of the first-generation drugs (Freedman, 2003); and quetiapine (QTP), an atypical antipsychotic drug that usually acts on both dopamine receptors and serotonin receptors (Martorell et al, 2006). Comparative proteomics of all mitochondrial proteins from the cerebral cortex and hippocampus of a rat model (Sprague-Dawley rats) in response to CPZ, CLZ and QTP antipsychotic medication demonstrated 14 differentially expressed different proteins.…”