br Acknowledgements The present study was
Acknowledgements The present study was supported by the Medical Science and Technology Program of Zhejiang Province2014KYA228 (Zhijun Zhou), 2016KYA195 (Jie Li) and 2017KY714 (Qingqing Xia); Zhejiang Provincial Natural Science Foundation of ChinaQ17H120001 (Jie Li); and Scientific Research Project of Taizhou Science and Technology Bureau in Zhejiang Province1402ky22 (Lingmin Zhang).
Introduction Schizophrenia (SZ), a chronic EVP4593 receptor disorder which affects 1% of the population, is one of the top 15 leading causes of disability worldwide (Vos et al., 2017). Clinical manifestations include positive symptoms (agitation, paranoia, delusions and hallucinations) and negative symptoms (apathy, social withdrawal and anhedonia) as well as deficits in various neurocognitive functions (Javitt and Sweet, 2015). Previous studies by our group and others have shown that mitochondrial dysfunction play a major role in the pathophysiology of the disease (Ben-Shachar, 2016, Chouinard et al., 2017, Manji et al., 2012, Prabakaran et al., 2004, Rajasekaran et al., 2015a). Imaging studies demonstrated reduction in mitochondrial originated high energy phosphates, such as ATP and phosphocreatine as well as in other cellular factors whose metabolism is strongly suggested to be linked to mitochondrial ATP production, in SZ-relevant brain structures (Fujimoto et al., 1992, Jayakumar et al., 2006, Volz et al., 2000). Genetic transcriptomic, proteomic, metabolomic molecular and biochemical studies, point to abnormalities in mitochondria in both the periphery and the brain in this disorder (Bergman and Ben-Shachar, 2016a, 2016b; Föcking et al., 2011, Rajasekaran et al., 2015b, Washizuka et al., 2006). Investigation of the mitochondrial oxidative phosphorylation system (OXPHOS) by our group and others, revealed alterations of the enzymatic activities of several complexes but specifically that of the first and largest complex, complex I (Co-I) in post-mortem brain specimens and in peripheral blood cells of SZ patients(Ben-Shachar and Karry, 2008, Haghighatfard et al., 2018, Karry et al., 2004, Rollins et al., 2018). The biosynthesis of heme (iron protoporphyrin IX), an essential iron-containing molecule, is an important function of the mitochondria (Ponka, 1999). The first and rate limiting step in heme biosynthesis pathway, as well as the last three steps, all take place in the mitochondria. Alterations in heme have been shown to affect the mitochondria. Both increase and decrease in heme levels were found to corrupt mitochondrial membrane potential (Higdon et al., 2012, Homedan et al., 2015). Though not fully understood, association between heme and Co-I, generating ∼40% of the proton-motive force needed for ATP production, has been suggested by two studies. A 52% decrease in Co-I activity was reported in a heme deficient mouse model (Homedan et al., 2014), and inhibition of Co-I was associated with decreased heme biosynthesis in HeLa cells (Gielisch and Meierhofer, 2015). Traditionally, heme was believed to merely control oxygen transfer. In the past few decades, however, heme was shown to take part in intricate processes such as signal transduction, assembly of protein complexes and regulation of transcription and translation, all of which are necessary for neuronal survival (Smith et al., 2011, Yang and Wang, 2010). One such example is regulation of protein synthesis by phosphorylation of eukaryotic initiation factor 2-alpha (eIF2α) via the mediator enzyme heme regulated inhibitor (HRI). HRI can bind four heme molecules; two structural irreversibly bound to the N-terminus domain, and two that reversibly bind at the C-terminus kinase insertion domain (Chefalo et al., 1998, Chen and London, 1995). When heme levels are low, the C-terminus domain is unoccupied resulting in auto-phosphorylation of HRI, which in turn phosphorylates eIF2α α subunit at Ser-51. Phosphorylated eIF2α (PeIFf2α) is inactive, hindering global translation and therefore an indicator of cellular heme levels (Chefalo et al., 1998). Heme has also been implicated in additional intricate processes such as mitochondrial proteolysis (Tian et al., 2011), acceleration of mRNA degradation (Cable et al., 1996, Hamilton et al., 1991), control of ion channels such as Ca2+-activated potassium channels (Tang et al., 2003) and binding nuclear receptor transcription factors such as Rev-erb α and β (Raghuram et al., 2007), nuclear receptors that function as transcription repressors.