**5.3 The mtDNA hypothesis for schizophrenia and its predictions**

Thus we propose here a new hypothesis which insists that the risk loci for schizophrenia are in the mtDNA.

Mitochondria are involved in a variety of major cellular events such as oxidative phosphorylation, free radical production and Ca2+ buffering, and play an active role in apoptosis. They possess two classes of antioxidant defense system (non-enzymatic and enzymatic), and structurally and functionally intact mitochondria serve as a *net sink* rather than a *net source* of reactive oxygen species (ROS) (Andreyev et al., 2005). ROS-defenses are severely undermined in structurally compromised mitochondria (Andreyev et al., 2005). Thus, mitochondrial dysfunction, presumably through imbalance of ROS production and removal (Andreyev et al., 2005), raises ROS emission (Esposito et al., 1999; Senoo-Matsuda et al., 2001) and causes intracellular oxidative stress.

Because abnormal mtDNA may cause mitochondrial dysfunction, the hypothesis predicts: (1) enhanced oxidative stress and disturbed energy metabolism in predisposed individuals, which may cause various pathogenic alterations such as genomic instability, aberrations in neurodevelopment, and the brain dysfunction. Furthermore, because mtDNA can be transmitted only through females and there is no link between the nuclear genome and the

rates at those loci are near the upper limit in the autosomes. All of them are located on 1q, while 4 resistance genes (*MHTFR*, *GRIK3*, *PDE4B*, *GSTM1*) are on 1p. \* schizophreniaassociated alleles; variants that could meet the criterion are shown in bold characters

rs1801133 T\*/C 0.3532 0.3211 1.15 0.032

rs6691840 G\*/T 0.2600 0.2226 1.25 0.037

rs910694 C/T\* 0.5780 0.5477 1.30 0.030

**rs2661319** A/**G\*** 0.4920 0.4744 **1.08 0.0176** 

rs1800896 G\*/A 0.3056 0.2657 1.42 0.040

rs841865 A/G\* 0.8434 0.8001 1.32 0.043 **rs1327175** G/**C\*** 0.92840 0.91243 1.32 **0.016** 

**rs3737597 A\***/G 0.03069 0.01735 1.80 **0.013 rs999710 A\***/G 0.3989 0.3819 1.07 **0.0170** 

Table 2. Schizophrenia-associated genes on the chromosome 1 that could meet the criterion

Thus we propose here a new hypothesis which insists that the risk loci for schizophrenia are

Mitochondria are involved in a variety of major cellular events such as oxidative phosphorylation, free radical production and Ca2+ buffering, and play an active role in apoptosis. They possess two classes of antioxidant defense system (non-enzymatic and enzymatic), and structurally and functionally intact mitochondria serve as a *net sink* rather than a *net source* of reactive oxygen species (ROS) (Andreyev et al., 2005). ROS-defenses are severely undermined in structurally compromised mitochondria (Andreyev et al., 2005). Thus, mitochondrial dysfunction, presumably through imbalance of ROS production and removal (Andreyev et al., 2005), raises ROS emission (Esposito et al., 1999; Senoo-Matsuda

Because abnormal mtDNA may cause mitochondrial dysfunction, the hypothesis predicts: (1) enhanced oxidative stress and disturbed energy metabolism in predisposed individuals, which may cause various pathogenic alterations such as genomic instability, aberrations in neurodevelopment, and the brain dysfunction. Furthermore, because mtDNA can be transmitted only through females and there is no link between the nuclear genome and the

**5.3 The mtDNA hypothesis for schizophrenia and its predictions** 

**(minor/major)** *mA mU OR d* 

allele\* 0.7546 0.7140 1.35 0.041

**Genes and** 

*MHTFR* 1p36.22

*GRIK3* 1p34.3

*PDE4B* 1p31.3

*GSTM1* 1p13.3

*RGS4* **1q23.3** 

*IL10* 1q32.1

*DISC1* **1q42.3** 

in the mtDNA.

**SNPs Location Allele** 

GSTM1\*0 ins-allele/del-

*PLXNA2* **1q32.2** A/G

et al., 2001) and causes intracellular oxidative stress.

mitochondrial genome, the mtDNA hypothesis predicts: (2) a higher maternal transmission of schizophrenia, and (3) positive associations between resistance genes and schizophrenia as well as negative associations between facilitating genes and schizophrenia (see 5.2). These predictions seem to be consistent with other major epidemiological findings and the results of the genetic and the pathophysiological studies to date.
