Postmortem studies on mitochondria in schizophrenia

Abstract

The aim of this paper is to provide a brief review of mitochondrial structure as it relates to function and then present abnormalities in mitochondria in postmortem schizophrenia with a focus on ultrastructure. Function, morphology, fusion, fission, motility, ΔΨmem, ATP production, mitochondrial derived vesicles, and mitochondria-associated ER membranes will be briefly covered. Pathology in mitochondria has long been implicated in schizophrenia, as shown by genetic, proteomic, enzymatic and anatomical abnormalities. The cortex and basal ganglia will be reviewed. In the anterior cingulate cortex, the number of mitochondria per neuronal somata in layers 5/6 in schizophrenia is decreased by 43%. There are also fewer mitochondria in terminals forming axospinous synapses. In the caudate and putamen the number of mitochondria is abnormal in both glial cells and neurons in schizophrenia subjects, the extent of which depends on treatment, response and predominant lifetime symptoms. Treatment-responsive schizophrenia subjects had about a 40% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen, while treatment resistant cases had normal values. A decrease in mitochondrial density in the neuropil distinguishes paranoid from undifferentiated schizophrenia. The appearance, size and density of mitochondria were normal in the nucleus accumbens. In the substantia nigra, COX subunits were affected in rostral regions. Mitochondrial hyperplasia occurs within axon terminals that synapse onto dopamine neurons, but mitochondria in dopamine neuronal somata are similar in size and number. In schizophrenia, mitochondria are differentially affected depending on the brain region, cell type, subcellular location, treatment status, treatment response and symptoms.

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

“…Mitochondria play a key role in cellular energy potential, calcium buffering, production of reactive oxygen species (ROS), they participate in regulation of apoptosis (42,43). The deficits of mitochondria found in the present study is consistent with alterations in mitochondrial ultrastructure and number (13)(14)(15)44), energy metabolism and oxidative stress, including the PFC (45)(46)(47). Defect of oxidative phosphorylation (reduced activity of complex IV) in the frontal cortex (48), altered expression of mitochondria-related genes including encoding respiratory chain components (49) have been reported in schizophrenia.…”

Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

“…The identification of a neuronal energetics module corroborates multiple lines of genetic 59 , metabolic 60 , anatomic 61 and functional 70 evidence linking mitochondrial dysfunction to SCZ.…”

“…Despite these differences, network analysis allowed us to identify a key point of convergence: two gene modules that were dysregulated in all CNVs in both the cortex and hippocampus. One of these dysregulated modules, the neuronal mitochondrial module cM2, overlaps with changes previously observed in SCZ and ASD in human post mortem brain [59][60][61] , highlighting its broader relevance to humans with these disorders and not only to those harboring these specific CNVs. The observation of this same biological process previously observed in human brain in three distinct mouse models is significant because it eliminates the explanation that the neuronal energetic dysfunction observed in humans reflects a post mortem artifact 62,63 .…”

“…Post-mortem brain studies show that mitochondrial structure and function are altered in SCZ, including a reduction in the number of mitochondria in neurons 27,61 . The association of SCZ and mitochondrial function is also supported by 28 mitochondrial related genes being contained among the 108 GWAS loci for SCZ, [71][72][73] which is consistent with our finding of enrichment of SCZ GWAS signals in cM2.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…A different level of lactates can be observed in the cerebrospinal fluid (CSF), where its increase indicates an intensified extra-mitochondrial anaerobic glucose metabolism [89]. Imaging techniques and metabolomics assessing mitochondrial functions have allowed the determination of metabolites dependent on oxidative stress or inflammation to identify pathological changes in the brains of patients with varying degrees of schizophrenia [90][91][92][93]. Analysis of mitochondrial membrane redox potential (via phosphorous magnetic resonance spectroscopy, P-MRS) of brain tissue and peripheral metabolomics (analysis of blood or fecal metabolites) of patients with schizophrenia revealed that oxidative modifications of key glycolytic enzymes appear in the affected areas of the brain (e.g., pyruvate dehydrogenase, fructose bisphosphate, 3-phosphoglyceraldehyde dehydrogenase, phosphoglycerate kinase-1, phosphoglycerate mutase) [94].…”