The psychiatric risk gene Cacna1c regulates mitochondrial function in cellular stress responses

Abstract

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…