Zishen Huoxue Decoction alleviates myocardial ischemia-reperfusion injury through dysregulation of endoplasmic reticulum-mitochondria homeostasis mediated by DUSP1-NDUFS4.

Astragaloside VI attenuates mechanical stress-induced cardiac remodeling through piezo1-VDAC1 dependent endoplasmic reticulum unfolded protein response.

Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis.

Mitochondrial metabolic reprogramming in macrophages is crucial in the development and progression of inflammation. Given vitamin A's antioxidant properties and its therapeutic effects on inflammation, this study aims to elucidate how vitamin A influences mitochondrial metabolic reprogramming in inflammatory states, specifically in periodontitis, through genetic bioinformatics and experimental methods. The study utilized the GSE16134 dataset from the Gene Expression Omnibus (GEO) database, focusing on human periodontitis. Vitamin A-targeted genes (ATGs) were identified and analyzed using CIBERSORT to explore their role in inflammation. Cluster analysis revealed two phenotypes associated with ATGs, showing differential expression of genes like COX1, IL-1β, and STAT3, and immune activation patterns. Weighted Gene Co-expression Network Analysis (WGCNA) identified 145 markers correlated with ATG-guided phenotypes and inflammation. Machine learning models, combined with Gene Set Variation Analysis (GSVA), identified five key genes (RGS1, ACAT2, KDR, TUBB2A, TDO2) linked to periodontitis. Cell Type-Specific Enrichment Analysis (CSEA) highlighted macrophages as critical in metabolic reprogramming, validated by external datasets with an AUC of 0.856 in GSE10334 and 0.750 in GSE1730678. Experimental validation showed vitamin A's role in suppressing endoplasmic reticulum stress and altering mitochondrial dynamics, as well as metabolic reprogramming influencing inflammation via the STAT3 pathway in RAW 264.7 cells. The study identified 13 differentially expressed ATGs in periodontitis, showing strong correlations with inflammation, particularly in plasma cells, macrophages, dendritic cells, neutrophils, and mast cells. Two ATG-guided phenotypes were identified, differing in gene expression and immune activation. WGCNA and machine learning models identified 145 markers and five key genes associated with periodontitis. GSVA and CSEA analyses highlighted the JAK-STAT pathway and macrophage involvement in metabolic reprogramming. Experimental data confirmed vitamin A's effects on mitochondrial dynamics and metabolic reprogramming through the STAT3 pathway. The study demonstrates that vitamin A's therapeutic effect on periodontitis is mediated through JAK-STAT pathway-guided mitochondrial metabolic reprogramming in macrophages. It identifies two genetic and immune-related phenotypes and five genetic identifiers associated with periodontitis risk.

BackgroundAcute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.MethodThis study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.ResultsTMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.ConclusionTMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.Graphical

The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.

Obese individuals are both insulin resistant and have high levels of circulating free fatty acids (FFAs). In cell culture, saturated but not unsaturated fatty acids induce endoplasmic reticulum (ER) stress. We hypothesized that chronic exposure to low dose fatty acids would significantly attenuate the acute stress response to a saturated fatty acid challenge and that unsaturated fatty acids (oleate) would be more protective than saturated fatty acids (palmitate). The ER stress response to palmitate was reduced after low dose fatty acid exposure in human hepatoma cells. Palmitate and oleate gave distinctive transcript responses, both acutely and after chronic low dose exposure. Differentially regulated pathways included lipid, cholesterol, fatty acid, and triglyceride metabolism, and IkappaB kinase and nuclear factor kappaB kinase inflammatory cascades. Oleate reduced palmitate-induced changes significantly more than low dose palmitate and completely blocked palmitate-induced phosphoinositide 3 kinase inhibitor (PIK3IP1) as well as induction of GADD45A and B. These changes are predicted to alter the PI3 kinase pathway and the pro-apoptotic p38 MAPK pathway. We recapitulated the oleate response by small interfering RNA-mediated block of PIK3IP1 stimulation with palmitate and significantly protected cells from palmitate-mediated ER stress. We show that transcriptional responses to oleate and palmitate are distinct, broad, and often discordant. We identified several potential candidates that may direct the transcriptional networks and demonstrate that PIK3IP1 partially accounts for the protective effects of oleate.

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability.

Cerebellar and multi-system metabolic reprogramming associated with trauma exposure and post-traumatic stress disorder (PTSD)-like behavior in mice

Mitochondrial metabolism and succinylation-related gene signatures for predicting prognosis and drug resistance in colon adenocarcinoma.

Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics-including fission-fusion balance and mitophagy-between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K-AKT-mTOR, AMPK-PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS-STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH-glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor-stroma metabolic cooperation and overcome treatment resistance in colorectal cancer.

Hepatic ischemia and reperfusion (IR) injury is a common complication in clinical practice. Endoplasmic reticulum (ER) stress and autophagy are the key factors in the process of hepatic IR injury. The vitamin D receptor (VDR) can mediate ER stress and autophagy; however, it can also mitigate IR injury. The relationship between VDR, ER stress, and autophagy in hepatic IR injury is unknown. VDR knockout mice and wild-type littermates underwent 70% liver ischemia (90 min) and reperfusion (6 h). To observe the effect of autophagy in the relationship with VDR and ER stress in hepatic IR injury, the autophagy agonist rapamycin and its inhibitor chloroquine were used in the study. Meanwhile, RAW264.7 cells were studied in vitro to verify the relationship between VDR, autophagy, and ER stress. VDR was involved in hepatic IR injury and its activation reduced liver injury and inhibited an inflammatory response. ER stress took part in the liver injury during the process of IR. Meanwhile, VDR activation was found to inhibit inflammation by ER stress, and vice versa. Furthermore, autophagy was the connection between VDR and ER stress. After treatment with rapamycin or chloroquine, the effect of VDR activation or VDR silencing in ER stress was partially reversed. The same tendency was observed in vitro. ER stress and autophagy are important mechanisms of hepatic IR injury. VDR can regulate ER stress through autophagy and then protect the liver from IR injury.

Excess 17β estradiol (E2) is a risk factor of breast cancer. Previously, we have reported that E2 through influencing mitochondria by unknown mechanism contribute to the estrogen induced breast carcinogenesis. The aim of this study was to evaluate the mitotoxic and cytotoxic effects of normal O. Majorana organic extract (OME) as well as PEGylated nanoconjugate of OME with triphenylphosphonium (P-OME) against human breast epithelial and cancer cell lines. Origanum majorana, commonly known as marjoram, is a perennial herb, which is widely used in the Middle East as a spice. It has been shown to possess extensive range of biological activity, including antioxidant, anti-inflammatory, and anti-tumor growth effects. Interestingly, the anticancer potential of O. Majorana against breast cancer remains largely unexplored. Here, we investigated the anticancer effect of O. Majorana on three breast cell lines. We also used triphenylphosphonium (TPP) cation to check whether an imbalance in mitochondrial bioenergetics, in part, may be responsible for estrogen induced growth of breast cancer. Determination of cell density (cell survival) by SRB and mitochondrial metabolic activity by MTT assays showed that both OME and P-OME reduced growth of MDA-MB-231 and MCF-7 cells, but no effect on normal breast epithelial MCF-10A cells. OME and TPP blocked E2-induced increases of cell survival, metabolic activity and proliferation of breast cancer MCF-7 cells. E2 treatment increased MitoTracker® Red 580 labeling, indicating E2 treatment increased MCF7 cells mitochondrial mass. We observed a several fold increase in mitochondrial transcription factor A (TFAM) DNA binding activity as early as 3 hrs in treated MCF7 cells. DNA synthesis was inhibited in E2-exposed MCF7 cells by the silencing of TFAM. To discern whether a decrease in ATP production may be responsible for the E2-induced growth signaling, we measured the ATP present in the MCF7 cells. Our data showed that the ATP levels in E2 treated cells were very similar to control cells. E2 treatment of MCF-7 cells increased mRNA and protein levels of BNIP3 involved in mitophagy/autophagy. Together these data suggest that a carcinogenic concentration of E2 may modify mitochondrial dynamics, mitophagy, biogenesis and metabolism. In summary, our results demonstrated for the first time that OME was able to inhibit estrogen-induced growth of MCF-7 cells in a time- and concentration-dependent manner. Our results also demonstrated that P-OME nanoconjugate compared to OME was far more effective in exerting its cytotoxic effect through the induction of growth arrest, mitochondrial metabolic activity, senescence, apoptosis and autophagic cell death in the highly metastatic triple negative MDA-MB-231 cells. Our findings offer a new perspective on the utility of O. Majorana plant extract to be developed as a new alternative medicinal therapy against breast tumors. Citation Format: Mohannad Garoub, Jayanta Das, Stanislaw Wnuk, Deodutta Roy. Origanum majorana organic extract induces senescence and autophagic cell death in breast cancer cells through influencing mitochondrial metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4061.

The global burden of heart failure following myocardial ischemia‐reperfusion (IR) injury is a growing problem. One pathway that is key to understanding the progression of myocardial infarction and IR injury is the endoplasmic reticulum (ER) stress pathway, which contributes to apoptosis signaling and tissue death. The role of calreticulin in the progression of ER stress remains controversial. We hypothesized that calreticulin induction drives proapoptotic signaling in response to ER stress. We find here that calreticulin is upregulated in human ischemic heart failure cardiac tissue, as well as simulated hypoxia and reoxygenation (H/R) and thapsigargin‐mediated ER stress. To test the impact of direct modulation of calreticulin expression on ER stress‐induced apoptosis, human cardiac‐derived AC16 cells with stable overexpression or silencing of calreticulin were subjected to thapsigargin treatment, and markers of apoptosis were evaluated. It was found that overexpression of calreticulin promotes apoptosis, while a partial knockdown protects against the expression of caspase 12, CHOP, and reduces thapsigargin‐driven TUNEL staining. These data shed light on the role that calreticulin plays in apoptosis signaling during ER stress in cardiac cells.