Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Abstract

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; v) decreased high-energy phosphates and decreased pH in the brain; and vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation

“…Mitochondrial dysfunction has been widely associated with psychiatric disorders (reviewed in (49)) and hDISC1 is one of the few susceptibility genes found till date that reinforces this association. Although hDISC1 is enriched in the mitochondria (5), the relationship of its mitochondrial function with the pathogenesis of the disease is still under debate.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…In addition to cellular evidence, changes in the expression of genes with known importance for developmental processes-including cellular migration, synaptogenesis, synaptic maintenance, cell signaling, glia, immune regulation, and mitochondrial function-have been found in postmortem tissue from patients with schizophrenia (Arion et al, 2007(Arion et al, , 2010Clay et al, 2010;Hakak et al, 2001;Harrison and Weinberger, 2005;Horvath and Mirnics, 2014a, b;Jaaro-Peled et al, 2009;Lewis et al, 2005;McGlashan and Hoffman, 2000;Middleton et al, 2002;Mirnics et al, 2000Mirnics et al, , 2001bMirnics and Pevsner, 2004;Roussos et al, 2012). Importantly, multiple studies report expression changes in GABA system-related transcripts, including altered expression of GABA-synthesizing enzymes, glutamic acid decarboxylase 1 and 2 (GAD1 and GAD2, discussed in the next section), interneuronexpressed proteins and neuropeptide genes (PV, CCK, NPY, SST, and CB) (Hashimoto et al, 2003(Hashimoto et al, , 2008aHoftman et al, 2013;Iritani et al, 2000;Kuromitsu et al, 2001;Maldonado-Aviles et al, 2009;Mellios et al, 2009;Volk et al, 2012), GABA receptor subunits (GABRA1-2, GABRA4-6, and GABRD) (Benes et al, 1992;Hashimoto et al, 2008a, b;Hoftman et al, 2013;Maldonado-Aviles et al, 2009;Volk et al, 2002b), and interneuron development-and maintenance-related mRNAs (GABA transporter 1, sodium potassium chloride cotransporter 1 (NKCC1), and KCC2) Fish et al, 2011;Hashimoto et al, 2008a, b;Hoftman et al, 2013;Hyde et al, 2011;Volk et al, 2002b).…”

The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

“…50 Mitochondrial function, which involves ATP production, reactive oxygen species homeostasis, and apoptosis regulation, is also altered. 51,52 Medications used in the treatment of these disorders have an influence on mitochondria, with mood stabilizers (e.g., lithium and valproate) reverting some of these abnormalities, which could explain the beneficial effects of these agents. 53,54 Curiously, antipsychotics may have the opposite effect and impair mitochondrial function.…”