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NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia

Molecular Psychiatry volume 25, pages 805–820 (2020)Cite this article

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Abstract

Mitochondria together with other cellular components maintain a constant crosstalk, modulating transcriptional and posttranslational processes. We and others demonstrated mitochondrial multifaceted dysfunction in schizophrenia, with aberrant complex I (CoI) as a major cause. Here we show deficits in CoI activity and homeostasis in schizophrenia-derived cell lines. Focusing on a core CoI subunit, NDUFV2, one of the most severely affected subunits in schizophrenia, we observed reduced protein level and functioning, with no change in mRNA transcripts. We further show that NDUFV2 pseudogene (NDUFV2P1) expression is increased in schizophrenia-derived cells and in postmortem brain specimens. In schizophrenia and controls pooled samples, NDUFV2P1 level demonstrated a significant inverse correlation with NDUFV2 pre- and matured protein level and with CoI-driven cellular respiration. Our data suggest a role for a pseudogene in its parent-gene regulation and possibly in CoI dysfunction in schizophrenia. The abnormal expression of the pseudogene may be one element of a vicious circle in which CoI deficits lead to mitochondrial dysfunction potentially affecting genome-wide regulation of gene expression, including the expression of pseudogenes.

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Acknowledgements

The authors thank Liat Linde, Ph.D., Dr. Nili Avidan, Ph.D., and Ronit Hod, Ph.D. from The Genomics Core Facility at the Rappaport Faculty of Medicine, Technion, for transcriptomic and data analysis services.

Funding

This study was supported by grants from the Israel Science Foundation-ISF (1295/11).

Author contributions

OB, RK, and DB-S conceived the experiments. OB, RK, and JM performed the experiments. OB and DB-S wrote the manuscript. DB-S secured funding. All authors contributed to and approved the final manuscript.

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  1. Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion—Israel Institute of Technology, Haifa, Israel

    Oded Bergman, Rachel Karry, Jumana Milhem & Dorit Ben-Shachar

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Bergman, O., Karry, R., Milhem, J. et al. NDUFV2 pseudogene (NDUFV2P1) contributes to mitochondrial complex I deficits in schizophrenia. Mol Psychiatry 25, 805–820 (2020). https://doi.org/10.1038/s41380-018-0309-9

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