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

Abstract

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.

Mitochondria, Microglia, and the Immune System—How Are They Linked in Affective Disorders?

“…CACNA1C codes for the α1c subunit of the L-type Ca 2+ channel (LTCC) Cav1.2, and has been identified by several genome-wide association studies as one of the strongest and most replicable risk factors for MDD and BD (128). In cultured mouse neuronal cells, reduction of CACNA1C expression or pharmacological inhibition of LTCC prevented excessive ROS formation, mitochondrial damage and ATP depletion, and rescued the neurons from cell death in a model of oxidative stress (129, 130). Our data corroborate earlier reports demonstrating that CACNA1C depletion or pharmacological LTCC inhibition was associated with antidepressant-like behavior and resilience to chronic stress, while activation of CACNA1C was detrimental for synaptic plasticity and cognitive functions (131, 132).…”

Regulation of Adult Neurogenesis in Mammalian Brain

“…Indeed, TAp73 directly regulates the expression of the cytochrome C oxidase subunit 4 (COX4I1), a mitochondrial protein from the complex IV, which is essential for energy supply in neurons [ 172 , 173 ]. NRF2 deletion affects the proliferation capacity of NSCs from SGZ and impairs neuronal differentiation [ 174 ] and the psychiatric susceptibility gene Cacna1c also promotes mitochondrial resilience to oxidative stress in neurons [ 175 ].…”

Psychiatric risk gene Cacna1c determines mitochondrial resilience against oxidative stress in neurons

“…Our recent findings published in Cell Death Discovery provide novel insight into a gene × stress interaction by showing that reduced Cacna1c expression mediated neuroprotective effects against oxidative stress, predominantly at the level of mitochondria 8 . In this study, we used immortalized mouse hippocampal HT22 cells, a well-established model system to investigate glutamate-induced oxidative stress, which reflects a common cellular response to environmental stress 9 .…”

“…This effect is likely attributed to reduced calcium influx through plasma membrane-localized Ca V 1.2 channels. Moreover, both Cacna1c knockdown and pharmacological LTCC inhibition led to altered Ca V 1.2-dependent gene transcription regulation, thereby suppressing the enhanced expression of the inner mitochondrial membrane calcium uptake protein MCU upon glutamate exposure 8 . 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.…”