Upstream Pathways Controlling Mitochondrial Function in Major Psychosis

Machado, Alencar Kolinski; Pan, Alexander; Silva, Tatiane Morgana da; Duong, Angela; Andreazza, Ana Cristina

doi:10.1177/0706743716648297

Cited by 25 publications

(18 citation statements)

References 127 publications

(206 reference statements)

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“…Mitochondrial dysfunction is commonly observed in other major psychiatric disorders such as bipolar disorder (BP) and major depression (MDD). [ 145 ] For example, mitochondrial dysfunction was commonly observed in transcriptomic and proteomic analysis of postmortem brain tissues in people with SCZ, BP, and MDD. [ 146 ] In addition, mitochondrial respiration abnormalities were observed in PBMCs of people with MDD [ 147 ] as well as in BP iPSC‐derived neurons.…”

Section: Mitochondrial Dysfunction In Other Psychiatric Disordersmentioning

confidence: 99%

Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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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.

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Section: Mitochondrial Dysfunction In Other Psychiatric Disordersmentioning

confidence: 99%

Mitochondrial Dysfunction in Schizophrenia

Chung

2020

BioEssays

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“…Under normal circumstances, endogenous antioxidants such as glutathione (GSH), neutralize these factors and protect human tissues from excess damage [58]. Without sufficient antioxidant levels to keep ROS under control, neurotoxicity can occur through oxidation of macromolecules such as DNA, proteins, and fats, and though the activation of cell signalling pathways that alter cell behaviour [59]. Over time, these changes might lead to some of the structural and functional alterations that are seen in psychosis [60].…”

Section: Oxidative Stress and Psychosismentioning

confidence: 99%

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

Barron

Hafizi

Andreazza

et al. 2017

IJMS

132

101

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Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-D-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.

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“…Moreover, dihydropyridine compounds with good central nervous system (CNS) penetration, such as nimodipine showed promising mood stabilizing effects in humans with affective disorders, suggesting that LTCC antagonists represent an additional option in the pharmacotherapy of psychiatric diseases, and especially patients carrying the CACNA1C risk SNP could benefit from this alternative treatment strategy 13 , 43 , 52 . Elevated cytosolic calcium levels, which may be associated with the CACNA1C risk SNP rs 1006737, represent a major upstream pathway that impairs mitochondrial function in BD 53 . In this regard, it has been reviewed recently that systemic administration of the DHP isradipine suppresses cytosolic calcium transients, increases mitochondrial mass and lowers mitophagy in dopaminergic neurons 54 .…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells

Michels

Ganjam

Martins

et al. 2018

Cell Death Discovery

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Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified CACNA1C as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affective disorders also involves diverse environmental risk factors such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events. At the cellular level, such environmental influences may activate oxidative stress pathways, thereby altering neuronal plasticity and function. Mitochondria are the key organelles of energy metabolism and, further, highly important for the adaptation to oxidative stress. Accordingly, multiple lines of evidence including post-mortem brain and neuro-imaging studies suggest that psychiatric disorders are accompanied by mitochondrial dysfunction. In this study, we investigated the effects of Cacna1c downregulation in combination with glutamate-induced oxidative stress on mitochondrial function, Ca2+ homeostasis, and cell viability in mouse hippocampal HT22 cells. We found that the siRNA-mediated knockdown of Cacna1c preserved mitochondrial morphology, mitochondrial membrane potential, and ATP levels after glutamate treatment. Further, Cacna1c silencing inhibited excessive mitochondrial reactive oxygen species formation and calcium influx, and protected the HT22 cells from oxidative cell death. Overall, our findings suggest that the GWAS-confirmed psychiatric risk gene CACNA1C plays a major role in oxidative stress pathways with particular impact on mitochondrial integrity and function.

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Upstream Pathways Controlling Mitochondrial Function in Major Psychosis

Cited by 25 publications

References 127 publications

Mitochondrial Dysfunction in Schizophrenia

Mitochondrial Dysfunction in Schizophrenia

Neuroinflammation and Oxidative Stress in Psychosis and Psychosis Risk

Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells

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