The psychiatric risk gene Cacna1c regulates mitochondrial function in cellular stress responses
Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness, and their pathophysiology involves complex interactions between genetic and environmental risk factors. However, the underlying mechanisms explaining how genetic and environmental...
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|Summary:||Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness, and their pathophysiology involves complex interactions between genetic and environmental risk factors. However, the underlying mechanisms explaining how genetic and environmental alterations affect the risk for psychiatric disorders are still largely unknown. Confirmed by several genome-wide association studies over the past ten years, CACNA1C represents one of the strongest and most replicable psychiatric risk genes. Besides genetic predispositions, environmental influences such as childhood maltreatment or chronic stress also contribute to disease vulnerability. In addition, increasing evidence suggests a crucial role for mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation in the development of major neuropsychiatric disorders. Furthermore, mitochondrial dysfunction in peripheral blood mononuclear cells (PBMCs) is currently being discussed as a potential biomarker for affective disorders supporting early diagnosis, control of disease progression, and evaluation of treatment response.
In a translational setting, the present project focused on the effects of defined gene-environment interactions on brain mitochondrial integrity and function in order to provide new insights into pathophysiological mechanisms of affective disorders and to identify novel therapeutic targets with potential relevance for future treatment strategies.
Using immortalized mouse hippocampal HT22 cells, a well-established model system to investigate glutamate-mediated oxidative stress, it was demonstrated that both siRNA-mediated Cacna1c gene silencing and L-type calcium channel (LTCC) blockade with nimodipine significantly prevented the glutamate-mediated rise in lipid peroxidation, excessive ROS formation, collapse of mitochondrial membrane potential, loss of ATP, reduction in mitochondrial respiration, and ultimately neuronal cell death. Moreover, both Cacna1c knockdown and pharmacological LTCC inhibition altered CaV1.2-dependent gene transcription, thereby suppressing the glutamate-induced expression of the inner mitochondrial membrane calcium uptake protein MCU. Accordingly, downregulation of Cacna1c substantially diminished the elevation in mitochondrial calcium levels after glutamate treatment. In the employed paradigm of oxidative glutamate toxicity, Cacna1c depletion also protected against detrimental mitochondrial fission and stimulated mitochondrial biogenesis without affecting mitophagy, thus promoting the turnover of mitochondria and preventing the accumulation of dysfunctional mitochondria in neuronal HT22 cells. These data imply that upstream genetic modifications, e.g. reduced CACNA1C expression, converge to control mitochondrial function, resulting in cellular resilience against oxidative stress.
In primary cortical rat neurons, heterozygous Cacna1c knockout partially reduced Cacna1c expression but had no impact on either initial increase in [Ca2+]i or delayed perturbations in mitochondrial bioenergetics, ATP levels, and cell viability in response to glutamate-mediated excitotoxicity. Furthermore, Cacna1c mRNA and protein expression levels were subject to strong regulation and degradation in this model of neuronal excitotoxicity. Partial neuroprotection against long-term glutamate toxicity by pharmacological LTCC blockade highlighted a potential dose-effect-dependency and the involvement of LTCCs in this cell death pathway.
In primary rat microglia cultures, both Cacna1c haploinsufficiency and nimodipine treatment were associated with reduced morphological changes and glycolytic metabolism upon lipopolysaccharide (LPS) stimulation. The LPS-induced shift from oxidative phosphorylation towards glycolysis seems essential for the inflammatory response, since the downstream release of NO, IL-1α, IL-1β, IL-6, IL-10, and TNF-α was also decreased in heterozygous Cacna1c as well as nimodipine-treated microglial cells. These results indicate a major functional role for CaV1.2-dependent signaling in the pro-inflammatory activation of microglia, the innate immune cells of the central nervous system.
By simulating the interaction of psychiatric disease-relevant genetic and environmental factors in vivo, the present study additionally evaluated their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment during the juvenile developmental period. In this specific gene-environment setting, isolated mitochondria from prefrontal cortex and hippocampus, both representing particularly susceptible brain regions in neuropsychiatric disorders, did not reveal considerable differences in mitochondrial bioenergetics, respiratory chain complex protein levels, superoxide formation, and membrane potential between the investigated conditions.
Finally, mitochondrial function was investigated in human PBMCs from probands recruited in the Marburg/Münster Affective Disorders Cohort Study (MACS). However, neither a family history of psychiatric disorders nor an experience of maltreatment during childhood had a significant effect on mitochondrial superoxide levels and respiratory parameters in PBMCs from healthy female subjects. Consequently, further research is required in order to shed more light on the early pathological mechanisms underlying neuropsychiatric disorders.
Overall, the present findings suggest that the GWAS-confirmed psychiatric risk gene CACNA1C plays a significant role in oxidative stress as well as neuroinflammatory pathways with particular impact on mitochondrial integrity and function, thereby adding to a better understanding of the intracellular processes likely involved in the pathophysiology of CACNA1C-associated disorders. Thus, modulating L-type calcium signaling may offer an effective therapeutic strategy in psychiatric disorders, where neuronal atrophy and inflammation contribute to disease pathophysiology.|
|Physical Description:||143 Pages|