Mammalian AKT, the Emerging Roles on Mitochondrial Function in Diseases.

Mitochondrial dysfunction may play a crucial role in various diseases due to its roles in the regulation of energy production and cellular metabolism. Serine/threonine kinase (AKT) is a highly recognized antioxidant, immunomodulatory, anti-proliferation, and endocrine modulatory molecule. Interestingly, increasing studies have revealed that AKT can modulate mitochondria-mediated apoptosis, redox states, dynamic balance, autophagy, and metabolism. AKT thus plays multifaceted roles in mitochondrial function and is involved in the modulation of mitochondria-related diseases. This paper reviews the protective effects of AKT and its potential mechanisms of action in relation to mitochondrial function in various diseases.

Crocin-I alleviates the depression-like behaviors probably via modulating "microbiota-gut-brain" axis in mice exposed to chronic restraint stress.

BACKGROUND: Depressive disorder is rapidly advancing in the worldwide, and therapeutic strategy through "gut-brain" axis has been proved to be effective. Crocin, has been found to have antidepressant activity. However, there is no thorough research for the effects of crocin-I (a major active component of crocin) on depression and its underlying mechanism. METHODS: We investigated the antidepressant effect of six-week oral administration of crocin-I in a mice model of depression induced by four-week CRS. Based on the "microbiota-gut-brain" axis, we determined the effects of crocin-I administration on gut microbiota, intestinal barrier function, short chain fatty acids and neurochemical indicators. RESULTS: Administration of crocin-I at a dose of 40 mg/kg for six weeks mitigated depression-like behaviors of depressed mice as evidenced by behaviors tests. In addition, crocin-I reduced the levels of lipopolysaccharide (LPS), Interleukin-6and tumor necrosis factor-α (TNF-α) in serum and TNF-α expression in the hippocampus, and increased the hippocampal brain-derived neurotrophic factor. Besides, 16 s rRNA sequencing revealed that crocin-I mitigated the gut microbiota dysbiosis in depressed mice as represented by the decreased abundance of Proteobacteria and Bacteroidetes, Sutterella spp. and Ruminococcus spp. and increased abundances of Firmicutes, Lactobacillus spp. and Bacteroides spp. Moreover, gas chromatography-mass spectrometry revealed that crocin-I reversed the decreased levels of short-chain fatty acids (SCFAs) in feces of depressed mice. Furthermore, crocin-I improved the impaired intestinal barrier by increasing expression of Occludin and Claudin-1, which contributed to the decreased LPS leakage. LIMITATIONS: Only the male mice were used; the dose-effect relationship should be observed. CONCLUSION: These results suggested that crocin-I effectively alleviated depression-like behavior, likely depended on the gut microbiota and its modulation of intestinal barrier and SCFAs.

Exposure to low concentration of trifluoromethanesulfonic acid induces the disorders of liver lipid metabolism and gut microbiota in mice.

Trifluoromethanesulfonic acid (TFMS) is the shortest chain perfluorinated compound. Recently, it has been identified as a persistent and mobile organic chemical with a maximum concentration of 1 µg/L in the environment. However, its toxicological mechanism remains unclear. In this study, to evaluate the liver and intestinal toxicity of TFMS in mammals, male mice were orally exposed to 0, 1, 10 and 100 µg/kg for 12 weeks. Our results showed that TFMS exposure reduced the epididymal fat weight in mice, caused the decrease of serum and liver triglyceride (TG) level and the increase of serum low density lipoprotein (LDL) level. Also, we observed the inflammatory cell infiltration in the liver of mice exposed to 10 µg/kg and 100 µg/kg TFMS, which was coupled with the increased mRNA expression levels of inflammatory factors such as COX2, TNF-α, IL-1ß in the liver. In addition, the mRNA expression levels of lipid metabolism-related genes (PPAR-α, ACOX, SCD1, PPAR-γ, etc.) were significantly decreased in the liver of mice after exposure to both doses of TFMS. We also found TFMS exposure caused the imbalance of cecal gut microbiota and change of cecal microbiota diversity. KEGG pathway predictions showed that the exposure of 100 µg/kg TFMS changed the synthesis and degradation of ketone bodies, benzoate degradation and several other metabolic pathways. Our findings indicated that TFMS exposure disturbed the liver lipid metabolism possibly via altering the gut microbiota.

Depression-like behaviors are accompanied by disrupted mitochondrial energy metabolism in chronic corticosterone-induced mice.

Stress exerts its negative effects by interference with mitochondrial energy production in rodents, and is able to impair mitochondrial bioenergetics. However, the underlying mechanism that stress hormone impacts depression-like behaviors and mitochondrial energy metabolism is still not well understood. Here, we investigated the changes of depression-like behaviors and mitochondrial energy metabolism induced by chronic corticosterone (CORT). The results showed that after treatment with CORT for 6 weeks, mice displayed depression-like behaviors, which were identified by tail suspension test, forced swimming test and open field test. Then, the livers were isolated and tested by RNA sequencing and metabolome analysis. RNA sequencing showed 354 up-regulated genes and 284 down-regulated genes, and metabolome analysis revealed 280 metabolites with increased abundances and 193 metabolites with reduced abundances in the liver of mice after CORT, which were closely associated with lipid metabolism and oxidative phosphorylation in mitochondria. Based on these findings, the changes of mitochondrial energy metabolism were investigated, and we revealed that CORT condition inhibited glycolysis and fatty acid degradation pathway, and activated synthesis of triacylglycerol, leading to the reduced levels of acetyl-CoA and attenuated TCA cycle. Also, the pathways of NAD+ synthesis were inhibited, resulting in the reduced activity of sirtuin 3 (SIRT3). Thus, all of these observations disrupted the function of mitochondria, and led to the decrease of ATP production. Our findings uncover a novel mechanism of stress on depression-like behaviors and mitochondrial energy metabolism in rodents.

Nicotinamide mononucleotide ameliorates the depression-like behaviors and is associated with attenuating the disruption of mitochondrial bioenergetics in depressed mice.

BACKGROUND: Nicotinamide mononucleotide (NMN) has been shown to stimulate oxidative phosphorylation in mitochondria and to improve various pathologies in patients and mouse disease models. However, whether NMN mediates mitochondrial energy production and its mechanism of action in depressed animals remain unclear. METHODS: Mice were subcutaneously injected with corticosterone (CORT; 20 mg/kg) each day for 6 weeks, while another group was given an additional dose of NMN (300 mg/kg) by oral gavage in the last 2 weeks. Then, transcriptome analyses, metabolome analyses and transient gene knockdown in primary mouse cells were performed. RESULTS: NMN administration alleviated depression-like behavior and the liver weight to body weight ratio in a mouse model of CORT-induced depression. Transcriptome and metabolome analyses revealed that in depressed mice, NMN reduced the mRNA expression of genes involved in fatty acid synthesis, stimulation of ß-oxidation and glycolysis, and increased production of acetyl-coenzyme A for the tricarboxylic acid cycle. Importantly, NMN supplementation increased NAD+ levels to enhance sirtuin (SIRT)3 activity, thereby improving mitochondrial energy metabolism in the hippocampus and liver of CORT-treated mice. Sirt3knockdown in primary mouse astrocytes reversed the effect of NMN by inhibiting energy production, although it did not affect NAD+ synthesis LIMITATIONS: Group sample sizes were small, and only one type of primary mouse cell was used CONCLUSION: These results provide evidence for the beneficial role of NMN in energy production and suggest that therapeutic strategies that increase the level of NMN can be an effective treatment for depression.

Antidepressant activity of crocin-I is associated with amelioration of neuroinflammation and attenuates oxidative damage induced by corticosterone in mice.

Depression is the leading cause of mental health-related disease globally, and it affects an estimated 300 million people worldwide. However, its physiological causes are not fully understood. Since available antidepressants fail to achieve complete disease remission, treating diversification of depression may be a useful contribution. Crocin, one of the main glycosylated carotenoids of saffron, has been found to have numerous pharmacological activities and has been reported to be associated with neuroprotective effects. However, the biological action of crocin-I, a major member of the crocin family, on depression-like behavior, neuroinflammation and oxidative damage in depressed animals remains unclear. The present study showed that crocin-I exerts significant antidepressant effects in a model of chronic corticosterone (CORT)-induced depression, as evidenced by the attenuation of depression-like behaviors in the open field test, forced swimming test and tail suspension test. The antidepressant activity of crocin-I was probably achieved through the suppression of neuroinflammation (IL-1ß) and oxidative stress in the mouse hippocampus. Additionally, the oral administration of crocin-I at a dose of 40 mg/kg reduced the CORT-induced accumulation of nicotinamide in the liver of the mice to improve the synthesis of NAD+, thereby stimulating the activity of SIRT3 deacetylase to elevate the activity of antioxidants such as superoxide dismutase 2 and glutathione reductase. Moreover, crocin-I reduced the levels of oxidative damage markers (reactive oxygen species and malonaldehyde) to rescue impaired mitochondrial function caused by CORT treatment, which was represented by electron transport chain and oxidative phosphorylation normality, and thus rescue ATP production to the level of that in wild-type mice. Our findings shed new light on the mechanism of action of crocin-I on depression-like behavior and oxidative stress in individuals stressed by perceived conditions.

Crocin-I ameliorates the disruption of lipid metabolism and dysbiosis of the gut microbiota induced by chronic corticosterone in mice.

Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. However, chronic treatment with GCs in clinical settings has a series of side effects, such as metabolic disorders, gut microbiota dysbiosis and neurological impairment. Therefore, searching for a functional substance that can alleviate these side effects is greatly meaningful to clinical patients. Crocin is the main active ingredient of saffron, which has been reported to have numerous pharmacological activities. However, the action of crocin-I, one major member of the crocin family, on the physiological mediation in the individuals receiving GC treatment remains unclear. In this study, we aimed to evaluate the efficacy of crocin-I on lipid metabolism and the gut microbiota in a mouse model of chronic corticosterone (CORT) treatment. Our findings showed that crocin-I reduced the levels of triglycerides and total cholesterol and the ratio of low density lipoprotein to high density lipoprotein in the serum of CORT-treated mice. In addition, transcriptome analysis revealed that crocin-I was effective in mediating the amelioration of lipid metabolism, mainly in fatty acid metabolism and steroid biosynthesis in CORT-treated mice. Moreover, metabolome analysis demonstrated that crocin-I could restore the disturbed metabolites in the liver of CORT-treated mice, most of which are long-chain fatty acids. Furthermore, high-throughput sequencing of 16s rRNA revealed that crocin-I could mitigate the dysbiosis of the gut microbiota caused by CORT at a dose of 40 mg kg-1, by resulting in a significant increase in the alpha diversity of the microbes in the cecal contents and a significant reduction in the abundance of Firmicutes, whereas by increasing the abundance of Bacteroidetes. These results indicated that oral administration of crocin-I could modify the composition of the gut microbiota and alleviate hepatic lipid disorder in mice treated with a high dose of GCs.

Exposure to jet lag aggravates depression-like behaviors and age-related phenotypes in rats subject to chronic corticosterone.

Our previous finding demonstrated that chronic corticosterone (CORT) may be involved in mediating the pathophysiology of premature aging in rats. Frequent jet lag increases the risk for many diseases, including obesity and type 2 diabetes, and is associated with the aging processes. However, the effect of jet lag on CORT-induced depression and its association with aging phenotypes remain unclear. In this study, the rats were exposed to both CORT and jet lag treatment, and the differences were analyzed and compared to rats with single CORT treatment. Our results showed that jet lag treatment aggravated CORT-induced depression-like behavior evidenced by sucrose intake test, forced swimming test, and open field test. Additionally, this treatment aggravated the shortening of telomeres, which possibly resulted in decreased telomerase activity, and downregulated the expression of telomere-binding factor 2 (TRF2) and telomerase reverse transcriptase compared to that in CORT rats, as revealed by quantitative real-time-polymerase chain reaction and western blot analysis, respectively. The shortening of telomeres may have been caused by increased oxidative stress, which was associated with the inhibition of sirtuin 3. Exposure to jet lag also aggravated the degeneration of mitochondrial functions, as shown by the decreases in the mRNA expression of COX1, ND1, and Tfam. Our findings provide physiological evidence that jet lag exposure may worsen stress-induced depression and age-related abnormalities.

Depression caused by long-term stress regulates premature aging and is possibly associated with disruption of circadian rhythms in mice.

Depression has been associated with circadian disruption and premature aging. Nevertheless, mechanisms underlying the link between long-term stress with premature aging and possible associations with circadian rhythms remain elusive. Here, mice were exposed to chronic mild stress for 16 weeks to induce depression-like symptoms, which were confirmed with the open field test, tail suspension test, and sucrose preference test. Then, the circadian rhythms of age-related indexes were compared between control and stressed mice. Long-term stress resulted in decreased body weight gain and locomotor activities, accompanied by losses of subcutaneous backside fat, decreased amounts of thigh muscle fibers, and shortened telomere length in hepatocytes. Stressed mice showed increased oxidative damage, causing impaired mitochondrial function and inflammatory responses, which may be mediated by the sirtuin 3 (SIRT3)-superoxide dismutase 2 (SOD2) signaling pathway. These changes may be associated with partial disruption of circadian rhythms or shifting phase values of some age-related indicators induced by long-term stress. These findings suggest that long-term exposure to stress may increase the risk of depression and regulate age-related phenotypes through associations with circadian rhythms.