**5.3.1 Mitochondrial dysfunction and enhanced oxidative stress in affected individuals**

The hypothesis predicts that patients with schizophrenia show mitochondrial dysfunction and enhanced oxidative stress.

Indeed, in the past decade, mitochondrial dysfunction and oxidative stress in schizophrenia has been suggested by several independent lines of evidence (for review, see Marchbanks et al., 1995; Ben-Shaffer, 2002; Wood et al., 2009); those include mitochondrial hypoplasia, disturbed oxidative phosphorylation, and altered mitochondrial-related gene expression in several cell lines.

The pioneering works in this field may be noteworthy (Utena & Niwa, 1992). As early as 1950, Hayashi, in a longitudinal study on glucose metabolites in blood sampled from the superior bulb of the internal jugular vein of schizophrenics, observed a decreased carbonic dioxide production in the brain and a higher level of lactate and glutathione, the brain's dominant free radical scavenger, in patients in an acute exacerbation of the illness. Utena and Ezoe (1951) reported a decreased glucose consumption *in vitro* in cortical brain tissues sampled from patients with schizophrenia who underwent prefrontal leukotomy. Takahashi (1953) confirmed this finding and emphasized the necessity of further investigations on oxidative phosphorylation in the brain tissue of schizophrenics. In line with those findings was the report by Stabenau et al. (1969), who observed, in a biochemical study of discordant monozygotic twin pairs, that lactate production and the lactate-pyruvate ratio were higher in the affected twins than the unaffected cotwins. More recently, Prabakaran et al. (2004), in a large-scale functional genomics study, suggested a state of intermittent or chronic hypoxic stress and mitochondrial dysfunction in the brain of patients with schizophrenia.
