Mitochondrial Dysfunction in Schizophrenia

Abstract

Schizophrenia (SCZ) is a severe neurodevelopmental disorder affecting 1% of populations worldwide with a grave disability and socioeconomic burden. Current antipsychotic medications are effective treatments for positive symptoms, but poorly address negative symptoms and cognitive symptoms, warranting the development of better treatment options. Further understanding of SCZ pathogenesis is critical in these endeavors. Accumulating evidence has pointed to the role of mitochondria and metabolic dysregulation in SCZ pathogenesis. This review critically summarizes recent studies associating a compromised mitochondrial function with people with SCZ, including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cell studies. This review also discusses animal models with mitochondrial dysfunction resulting in SCZ-relevant neurobehavioral abnormalities, as well as restoration of mitochondrial function as potential therapeutic targets. Further understanding of mitochondrial dysfunction in SCZ may open the door to develop novel therapeutic strategies that can address the symptoms that cannot be adequately addressed by current antipsychotics alone.

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

“…A number of genes involved in mitochondrial function and responsive to PGC-1α overexpression in human neuroblastoma cells [70] are reduced, including ATP5A1 [259,260], glutamic-oxaloacetic transaminase 1 (GOT1; [259]), IDH3A [260], and malate dehydrogenase 1 (MDH1; [260]). These findings are concordant with reports of mitochondrial dysfunction in autism (reviewed in [263] and [264]) and schizophrenia (reviewed in [265]). Transcriptional studies also reported decreased expression of PVALB [259,260], SYT2, NEFH, and glutamic acid decarboxylase 1 and 2 (GAD1 and GAD2) [259], indicating either the loss of expression of these markers and mitochondrial genes in existing interneuron populations or the loss of these neurons.…”

Oxidative Stress‐Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives

“…Ample evidence has been accumulated, indicating a multifaceted mitochondrial dysfunction in schizophrenia (reviewed in [ 198 , 200 , 201 ]). Primarily, morphological and functional abnormalities of mitochondria in schizophrenia were detected.…”

“…These changes may be associated with impaired gene expression. Indeed, the decreased expression of numerous mitochondria-related genes (encoding, for example, NADH-ubiquinone oxidoreductase core subunits V1, V2, and S1 and cytochrome c oxidase) was observed in postmortem brain tissues of patients with schizophrenia in smaller-scale studies [ 201 ]. As stated above, transcriptomic and proteomic studies in large samples also confirmed the impaired expression of mitochondrial genes in brain tissues [ 98 , 103 , 207 ].…”

“…Evidence also includes the genetic association of mitochondrial genes with schizophrenia. Among the 350 genes within 108 schizophrenia loci identified by GWAS [ 91 ], 22 are related to mitochondrial function [ 201 ]. For instance, the association of schizophrenia with the USMG5 gene encoding a small subunit of the mitochondrial ATP synthase (complex V), as well as with the SFXN2 gene encoding sideroflexin-2, which is involved in iron metabolism in mitochondria, has been shown [ 91 ].…”

“…Various animal models have shown that mitochondrial dysfunction leads to neurobehavioral abnormalities (reviewed in [ 201 ]). Ablation of the transcriptional coactivator PGC-1 α reduced the expression of the Ca-binding protein parvalbumin (PV) in the GABAergic interneurons and also disrupted evoked synaptic responses in mice [ 210 ].…”