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This study addresses the eventual consequence of cytochrome c oxidase (CytOx) inhibition by ATP at high ATP/ADP ratio in isolated rat heart mitochondria. Earlier, it has been demonstrated that the mechanism of allosteric ATP inhibition of CytOx is one of the key regulations of mitochondrial functions. It is relevant that aiming to maintain a high ATP/ADP ratio for the measurement of CytOx activity effectuating the enzymatic inhibition as well as mitochondrial respiration, optimal concentration of mitochondria is critically important. Likewise, only at this concentration, were the differences in ΔΨm and ROS concentrations measured under various conditions significant. Moreover, when CytOx activity was inhibited in the presence of ATP, mitochondrial respiration and ΔΨm both remained static, while the ROS production was markedly decreased. Consubstantial results were found when the electron transport chain was inhibited by antimycin A, letting only CytOx remain functional to support the energy production. This seems to corroborate that the decrease in mitochondrial ROS production is solely the effect of ATP binding to CytOx which results in static respiration as well as membrane potential.

Obesity—in which free fatty acid (FFA) levels are chronically elevated—is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.

The pathophysiology of neuropsychiatric disorders involves complex interactions between genetic and environmental risk factors. Confirmed by several genome-wide association studies, Cacna1c represents one of the most robustly replicated psychiatric risk genes. Besides genetic predispositions, environmental stress such as childhood maltreatment also contributes to enhanced disease vulnerability. Both, Cacna1c gene variants and stressful life events are associated with morphological alterations in the prefrontal cortex and the hippocampus. Emerging evidence suggests impaired mitochondrial bioenergetics as a possible underlying mechanism of these regional brain abnormalities. In the present study, we simulated the interaction of psychiatric disease-relevant genetic and environmental factors in rodents to investigate 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. Mitochondria were isolated from the prefrontal cortex and the hippocampus to evaluate their bioenergetics, membrane potential, reactive oxygen species production, and respiratory chain complex protein levels. None of these parameters were considerably affected in this particular gene-environment setting. These negative results were very robust in all tested conditions demonstrating that Cacna1c depletion did not significantly translate into altered bioenergetic characteristics. Thus, further investigations are required to determine the disease-related effects on brain mitochondria.

Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD.

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ. This article has an associated First Person interview with the first author of the paper.