Impaired heme metabolism in schizophrenia-derived cell lines and in a rat model of the disorder: Possible involvement of mitochondrial complex I.

Accumulating data point to heme involvement in neuropsychiatric disorders. Heme plays a role in major cellular processes such as signal transduction, protein complex assembly and regulation of transcription and translation. Its synthesis involves the mitochondria, which dysfunction, specifically that of the complex I (Co-I) of the electron transport chain is involved in the pathophysiology of schizophrenia (SZ). Here we aimed to demonstrate that deficits in Co-I affect heme metabolism. We show a significant decrease in heme levels in Co-I deficient SZ-derived EBV transformed lymphocytes (lymphoblastoid cell lines - LCLs) as compared to healthy subjects-derived cells (n = 9/cohort). Moreover, protein levels assessed by immunoblotting and mRNA levels assessed by qRT-PCR of heme catabolic enzyme, heme Oxygenase 1 (HO-1), and protein levels of heme downstream target phosphorylated eukaryotic initiation factor 2-alpha (Peif2a/eif2a) were significantly elevated in SZ-derived cells. In contrast, protein and mRNA levels of heme synthesis rate limiting enzyme aminolevulinic acid synthase-1 (ALAS1) were unchanged in SZ derived LCLs. In addition, inhibition of Co-I by rotenone in healthy subjects-derived LCLs (n = 4/cohort) exhibited an initial increase followed by a later decrease in heme levels. These findings were associated with opposite changes in heme's downstream target and HO-1 level, similar to our findings in SZ-derived cells. We also show a brain region specific pattern of impairment in Co-I subunits and in HO-1 and PeIF2α/eIF2α in the Poly-IC rat model of SZ (n = 6/cohort). Our results provide evidence for a link between CoI and heme metabolism both in-vitro and in-vivo suggesting its contribution to SZ pathophysiology.