Cardiolipin remodeling by ALCAT1 links hypoxia to coronary artery disease by promoting mitochondrial dysfunction.

Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining cardiac health. A loss of tetralinoleoyl cardiolipin (TLCL), the predominant cardiolipin species in the healthy mammalian heart, is implicated in the pathogenesis of coronary heart disease (CHD) through poorly defined mechanisms. Here, we identified acyl-coenzyme A:lysocardiolipin acyltransferase-1 (ALCAT1) as the missing link between hypoxia and CHD in an animal model of myocardial infarction (MI). ALCAT1 is an acyltransferase that promotes mitochondrial dysfunction in aging-related diseases by catalyzing pathological remodeling of cardiolipin. In support of a causative role of ALCAT1 in CHD, we showed that ALCAT1 expression was potently upregulated by MI, linking myocardial hypoxia to oxidative stress, TLCL depletion, and mitochondrial dysfunction. Accordingly, ablation of the ALCAT1 gene or pharmacological inhibition of the ALCAT1 enzyme by Dafaglitapin (Dafa), a potent and highly specific ALCAT1 inhibitor, not only restored TLCL levels but also mitochondrial respiration by attenuating signal transduction pathways mediated by hypoxia-inducible factor 1α (HIF-1α). Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa effectively mitigated CHD and its underlying pathogenesis, including dilated cardiomyopathy, left ventricle dysfunction, myocardial inflammation, fibrosis, and apoptosis. Together, the findings have provided the first proof-of-concept studies for targeting ALCAT1 as an effective treatment for CHD.

Rapamycin extends life and health in C57BL/6 mice.

Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment.

Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.

Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player in bacterial stress response and persistence. We reveal that (p)ppGpp activates global metabolic changes upon starvation, allowing survival by regulating GTP. Combining metabolomics with biochemical demonstrations, we find that (p)ppGpp directly inhibits the activities of multiple GTP biosynthesis enzymes. This inhibition results in robust and rapid GTP regulation in Bacillus subtilis, which we demonstrate is essential to maintaining GTP levels within a range that supports viability even in the absence of starvation. Correspondingly, without (p)ppGpp, gross GTP dysregulation occurs, revealing a vital housekeeping function of (p)ppGpp; in fact, loss of (p)ppGpp results in death from rising GTP, a severe and previously unknown consequence of GTP dysfunction.

Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction.

Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.