Sex differences in schizophrenia: estrogen and mitochondria

Schizophrenia (SCZ) is a neuropsychiatric disorder which displays sex differences in its clinical manifestations, including women presenting with later age at onset, less severe course, and better response to antipsychotics in comparison with men. Estrogen is a steroid hormone which, in addition to its role in females’ reproduction and sex characteristics, contributes to neuroprotection within the central nervous system.

In this context, there is compelling evidence that estrogen has a protective effect in females against the development of neuropsychiatric disorders, particularly SCZ. Estrogen is reported to influence several features of SCZ pathophysiology and to promote the observed sex-difference in the clinical outcomes between males and females. The molecular mechanisms by which estrogen affects SCZ are still largely unknown, but there is evidence that estrogen plays a role in synaptic plasticity, neurogenesis, and neurotransmission, as well as in modulating reactive oxygen species (ROS) burden in the brain [1]. Notably, each of these neurobiological mechanisms is disturbed in the brain of SCZ patients.

More recently, it has been reported that estrogen also modulates mitochondrial function [2]. Mitochondria are the main source of energy for most cellular activities. In the brain, mitochondria are also implicated in many neuronal processes reported to be involved in SCZ pathophysiology, and mitochondrial dysfunction is emerging as a risk factor for the disorder [3]. Over 1000 mitochondrial genes are encoded by the nuclear genome, and also, mitochondria contain their own small genome (mtDNA), which is exclusively maternally inherited. Interestingly, studies have revealed a stronger maternal inheritance of SCZ compared to paternal [4].

Mitochondria have sex-specific features, exhibiting distinct effects in males versus females, and these effects have strong links to neuroprotection. Briefly, studies in a variety of animal models have shown that females’ mitochondria have increased biogenesis and oxidative capacity, and greater antioxidant defense with (consequently) reduced generation of ROS, thus less release of mitochondrial apoptotic factors [5]. There is evidence that estrogen might be a key player in this mitochondrial sexual dimorphism. Several nuclear-encoded mitochondrial genes show specific DNA sequences that are targets of estrogen, called estrogen response elements (ERE). The strongest evidence is the finding that estrogen receptor beta binds to estrogen EREs in mtDNA, directly regulating its gene transcription. Moreover, with respect to direct biochemical connection for the role of estrogen in mitochondrial function, treatment of cells with estrogen protects against electron transport chain inhibitors [2]. However, the actions of estrogen on mitochondrial functioning that may underlie this hormone’s sex-specific effects on brain development and behavior in schizophrenia remain uninvestigated, and are an important target of research in animal models for the disease.

Overall, it appears that estrogen plays a role in SCZ pathophysiology and in protecting females against a more severe course of the disease, probably (but not exclusively) through its regulation of the mitochondrial system. A better understanding of the influence of estrogen on mitochondrial function in the context of SCZ will reveal new insights regarding the pathophysiology of the disease in males versus females. This new perspective will generate novel targets for drug discovery with potential to improve many of the SCZ clinical outcomes, as well as developing future preventive and therapeutic strategies.

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Acknowledgments

We would like to acknowledge the Judy and Larry Tanenbaum Family Foundation for their support to this study.

Funding

J.L.K. has been funded by Genome Canada, The Ontario Ministry of Research and Innovation, CIHR, a BBRF/NARSAD Distinguished Investigator Award, and the Judy and Larry Tanenbaum Foundation. J.L.K. has also received speaker honoraria and expenses from Eli Lilly, Novartis, and Shire, and consultant honoraria and expenses from Roche, and is a nonpaid member of the SAB of Assurex Health Inc.

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Correspondence to James L. Kennedy.

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Gonçalves, V.F., Cuperfain, A.B. & Kennedy, J.L. Sex differences in schizophrenia: estrogen and mitochondria. Neuropsychopharmacol 44, 216–217 (2019). https://doi.org/10.1038/s41386-018-0228-0

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