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Abstract

Background: Dysregulation of calcium (Ca2+) homeostasis and mitochondrial alterations have both been implicated in schizophrenia pathophysiology. Altered Ca2+ levels and abnormal expression of Ca2+-binding proteins have been suggested to contribute to mitochondrial dysfunction in SZ. Our lab has recently found alterations in subcellular localization and trafficking of glutamate receptors in SZ, suggesting endoplasmic reticulum (ER) dysfunction. The ER is a major calcium reservoir in the cell and regulates mitochondrial calcium levels through mitochondrial associated membranes (MAMs) at the ER-mitochondria interface. These specialized membrane domains are enriched for proteins that regulate calcium uptake and release. In this study, we hypothesized that abnormal calcium transport machinery at MAMs contributes to mitochondrial dysfunction evident in SZ.

Methods: We measured the transcript expression of 20 genes involved in calcium dynamics that are enriched in MAMs. Quantitative real-time PCR was used to measure mRNA levels from samples of dorsolateral prefrontal cortex (DLPFC) from matched pairs of SZ and comparison subjects (N = 14).

Results: Of 20 genes assessed, Ryanodine receptor 1 (RYR1), Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2), Mitofusin 2 (MFN2), and B-Cell CLL/Lymphoma 2 (BCL2) were found significantly increased in SZ.

Conclusion: PACS2 and MFN2 are involved in ER-mitochondria tethering necessary for Ca2+ transport via MAMs. BCL2 regulates ER Ca2+ levels and controls mitochondrial membrane permeability and RYR1 is a Ca2+ channel that mediates Ca2+ release to the cytoplasm. Normal expression of these 4 molecules is necessary for proper Ca2+ regulation at MAMs. Increased levels, as we here report, suggest that abnormal Ca2+ transport may contribute to altered mitochondrial function and dynamics seen in SZ. Our future experiments will examine the protein expression of these 4 genes.

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© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]
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