Inappropriate heme metabolism has been linked to
Inappropriate heme metabolism has been linked to several neuropsychiatric disorders. In the hippocampi of Alzheimer\'s disease (AD) patients, for example, heme was found to binds intracellular amyloid β (Aβ), resulting in reduced heme bioavailability and its functional deficiency (Atamna and Frey, 2004). Heme Oxygenase-1 (HO-1), the heme catabolic rate limiting enzyme, was found to be overexpressed in the cerebral cortex and hippocampus of individuals with AD (Barone et al., 2012, Smith et al., 1994), the substantia nigra of Parkinson\'s disease (PD) patients (Schipper et al., 1998) and its mRNA was overexpressed in the prefrontal cortex of patients with SZ (Prabakaran et al., 2004). These data suggest an increase in HO-1 activity in the pathophysiology of several neuropsychiatric disorders. Furthermore, neuroporphyria, a condition in which heme levels are scarce, is characterized by psychiatric manifestations several are similar to SZ such as psychosis, hallucinations and paranoia as well as anxiety, insomnia and depression (Anderson et al., 2001). As heme is associated with both neuropsychiatric pathology and the mitochondria, we hypothesize that alterations in Co-I may affect heme metabolism in SZ.
Discussion Mitochondrial dysfunction has been repeatedly reported in SZ, and genetic, molecular and biochemical impairments in Co-I are consistently reported in various Milnacipran HCl and somatic cells of SZ patients (Ben-Shachar et al., 1999; Bergman and Ben-Shachar, 2016a, Bergman and Ben-Shachar, 2016b; Cavelier et al., 1995, Dror et al., 2002, Gubert et al., 2013, Maurer et al., 2001, Prince et al., 1999). A major obstacle in SZ research is the limited accessibility of the brain. LCLs have been shown to retain many SZ-related abnormalities including those of the mitochondria and unlike fresh lymphocytes have been suggested as a medication-free peripheral cell model for SZ and other disorders (Gangadhar et al., 2004, Sei et al., 2007, Washizuka et al., 2009). Therefore, SZ- derived LCLs, which have repeatedly shown to have impaired Co-I activity and reduced oxygen consumption rates (Robicsek et al., 2018, Rosenfeld et al., 2011) were used in this study. It was previously shown that EBV viral load and ATP levels in LCLs used as covariates in gene expression analyses, can affect gene expression (Choy et al., 2008). We have previously shown that there was no significant difference in EBV viral load between our SZ and healthy subjects derived LCLs (Rosenfeld et al., 2011). In addition, in contrast to gene experiments in which every LCL is used once, we have repeated each experiment several times and used different LCLs, minimizing the effects of EBV viral load and ATP levels on our outcomes. Here we show that the CoI deficiency is associated with alterations in heme metabolism and signaling. In the SZ-derived cell lines a 20% reduction in cellular heme levels were observed, while its levels in SZ-derived isolated mitochondria was similar to the control. Reduced cellular heme is in complement with previous reports indicating reduced heme levels in disorders exhibiting SZ-like symptomology such as porphyria (Homedan et al., 2014) and Co-I deficiencies (Gielisch and Meierhofer, 2015). Unchanged mitochondrial heme is in line with unaltered protein and mRNA levels of the mitochondrial heme synthesis rate-limiting enzyme ∆-ALAS1 in SZ-derived cells and unaltered levels and activity of complex IV (Ben-Shachar et al., 1999), which contains two hemes, cytochrome a and a3. These data suggest that heme biosynthesis pathway is unaffected, while cytosolic heme metabolism is abnormal in SZ derived cells. Indeed, elevated HO-1 protein and mRNA were witnessed, suggesting increased heme degradation in these cells. It was previously shown that selective overexpression of HO-1 in astrocytes of GFAP HMOX1 transgenic mice resulted in subcortical mitochondrial autophagy and SZ-like behaviors (Song et al., 2012). In contrast, it was reported that overexpression of HO1 protects the heart from oxidative injury by regulating mitochondrial quality control, upregulating the expression of genes involved in mitochondrial biogenesis and fusion and downregulating those involved in fission (Hull et al., 2016). Other showed that in cells, inhibition of HO1 prevents mitochondria associated protection by an antioxidant (Duarte et al., 2018). In addition, a growing number of studies report alteration of HO-1 expression and activity in neuropsychiatric disorders (Barone et al., 2012, Prabakaran et al., 2004, Schipper et al., 1998, Smith et al., 1994). Taken together, these findings suggest an intricate mechanism underlying the reciprocal interaction between mitochondria or CoI and HO1 in general and in SZ in particular.