Dapagliflozin ameliorates myocardial ischemia/reperfusion injury by modulating EGFR signaling and targeting NCOA4-mediated ferritinophagy.

Oxytocin ameliorates cardiac hypertrophy by inhibiting mitochondrial dysfunction and pyroptosis via AMPK/PGC-1α /TFAM pathway.

Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.

Time-restricted feeding (TRF), which confines food intake to specific time periods without altering nutrient content or reducing calories, has shown promise in improving cardiometabolic health. This study tested whether a 2-wk TRF intervention during the active (dark) period could reverse long-term effects of a high-fat diet (HFD) on liver mitochondrial function, steatosis, and metabolism in mice. Male C57BL/6J mice were fed either a normal-fat diet (NFD, 10% kcal fat) or an HFD (45% kcal fat) ad libitum for 18 wk, followed by 2 wk of active period TRF. Assessments included whole body metabolism, gene expression, histopathology, plasma lipid levels, and mitochondrial bioenergetic function. Chronic HFD feeding abolished the day-night difference in the respiratory exchange ratio (RER), altered 24-h expression rhythms of clock, lipid, and mitochondrial metabolism genes in the liver, and eliminated diurnal variation in liver mitochondrial bioenergetics. TRF partially restored RER rhythmicity without altering body composition or reducing caloric intake in HFD mice. TRF also reset 24-h expression rhythms in clock and several metabolic genes, normalized liver and plasma triglyceride oscillations, and reduced small droplet macrosteatosis in the livers of HFD mice. Importantly, TRF improved liver mitochondrial respiration and reduced circulating levels of mitochondrial transcription factor A, a mitochondrially-derived damage-associated molecule pattern, indicating reduced mitochondrial injury in HFD mice. These findings suggest that TRF can rapidly reverse HFD-induced disruptions in metabolic and mitochondrial function, offering a promising new nonpharmacologic strategy for improving liver health in obesity-related metabolic disease.

Endothelial Arg2 regulates HIMM-induced mitochondrial hyperfission via affecting arginine metabolism.

Taurine restores oocyte quality by enhancing mitochondrial function in mice exposed to dibutyl phthalate during adolescence.

Mitochondrial dynamics play a crucial role in thyroid cancer progression by regulating apoptosis, metabolism, and oxidative stress. Ceritinib, a tyrosine kinase inhibitor, shows potential anticancer effects; however, its impact on mitochondrial function in thyroid cancer remains obscure. Herein, we aim to investigate the impact of ceritinib on the mitochondrial functionality in TPC-1 thyroid carcinoma cells and the underlying mechanism. Cell viability was assessed with the CCK-8 assay, and the cytotoxicity was determined by evaluation of the lactate dehydrogenase (LDH) release assay. Mitochondrial reactive oxygen species (ROS) were detected by MitoSOX Green staining. Enzyme-linked immunosorbent assay (ELISA) was applied for 8-hydroxydeoxyguanosine (8-OHdG) determination. Real-time PCR was employed for mRNA levels assessment, and western blotting was applied for protein levels. The morphology of mitochondria was evaluated by means of Mitotracker Red CMXRos staining. Ceritinib triggered mitochondrial oxidative stress, evidenced by elevated ROS and 8-OHdG levels, while suppressing manganese superoxide dismutase (Mn-SOD) activity. It also impaired mitochondrial respiration, ATP production, and Complex III activity, leading to dysfunction. Notably, ceritinib promoted mitochondrial fragmentation by enhancing dynamin-related protein 1 (Drp1) translocation to mitochondria, reducing l-OPA1 and increasing S-OPA1 levels, without altering mitofusins 1 and 2 (Mfn-1 and -2) expression. Mechanistically, ceritinib activated the Mitochondrial Calcium Uniporter (MCU)/calpain pathway, increasing MCU, calpain1/2, and calpain activity. Inhibition of MCU by RU360 reversed ceritinib-induced Drp1 mitochondrial translocation, fragmentation, and ATP depletion. Our findings reveal that ceritinib disrupts mitochondrial dynamics via the MCU/calpain/Drp1 axis. This study identifies a previously unreported mechanism for ceritinib in thyroid carcinoma, suggesting a novel therapeutic strategy.

Mitochondrial TRPV1 exacerbates cognitive deficits in sepsis-associated encephalopathy by driving microglial metabolic reprogramming.

Raising of mitogenic and anti-apoptotic agents - such as insulin, insulin-like growth factor type 1, and estrogen - during obesity and diabetes mellitus (types 1 and 2) favors the endometrial cancer (EC) development. Metformin, commonly used for treating type 2 diabetes, and resveratrol, a natural polyphenol, can both decrease cancer cell proliferation by modulating the PI3K/Akt/mTOR pathway. We evaluate the effects of metformin and/or resveratrol in an in vitro model of human type 1 endometrioid EC. Ishikawa cells were treated with 0.1 to 50mM of metformin and/or 0.1 to 75μM of resveratrol from 24h to 72h. Analyses assessed cell viability, cytotoxicity, caspases activation, mitochondrial function, cellular death, cell cycle, and the PI3K/Akt/mTOR pathway gene expression. In-silico analysis was conducted using Cytoscape. Metformin induced mitochondrial swelling, caspase-mediated apoptosis, and cell cycle arrest. Resveratrol decreased mitochondrial mass, cytotoxicity, and induced cell cycle arrest. Combined treatment with the highest concentrations reduced mitochondrial activity, cytotoxicity, and caspase activation while maintaining apoptotic features and cell cycle arrest. Resveratrol attenuated the toxic effects of metformin but it could be inducing a caspase-independent cell death in co-treated cells. Although in-silico analysis suggested potential molecular targets and interconnected mechanisms, lower concentrations did not alter PI3K/Akt/mTOR gene expression.

Investigating the therapeutic potential of nasal administration of mitochondria on blood-brain barrier integrity and vasogenic brain Edema in a rat ischemic stroke model.

Ginsenoside Rh4 activates AMPK and alleviates NFκB-mediated inflammation in hyperlipidemic hepatopathy.

Spermidine alleviates heat stress-induced deterioration of porcine oocytes.

Homoplantaginin ameliorates osteoarthritis by activating Sirt3/PINK1/Parkin signaling to promote mitophagy and attenuate inflammation in chondrocytes.

Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS), synthetic and resistant to degradation, are present at trace levels in municipal drinking water. PFAS exposure is associated with female infertility and developmental anomalies, yet how these compounds influence ovarian function and embryogenesis is not understood. Thus, the impact of exposure to PFAS via drinking water on oocyte viability and embryo development was examined. The local tap water was found to contain ∼3ng/L PFAS, primarily PFOS, PFOA, and PFHxS. Female mice were then given purified water containing 5ng/L or 50ng/L of these same three PFAS compounds or drinking fountain (tap) water for 4 weeks or 6 months. Ovulation, oocyte quality, embryo development and fetal weight were analyzed across three generations. Embryos from PFAS-exposed females (5ng/L or 50ng/L PFAS or tap water) exhibited impaired mitochondrial function, DNA damage and fewer cells, and reduced fetal weight. Embryo phenotypes were similar whether females were PFAS-exposed for 4 weeks, 6 months or just the first 4 weeks of the 6 months. Offspring drank purified water, yet fertility analysis showed similar embryonic and neonatal phenotypes in the F1 'daughters' of the PFAS-exposed females, and in the embryos of F2 females ('granddaughters' of PFAS-exposed females). To determine causality and whether defects are reversible, embryos were treated mitochondria-modulating compounds, with responses indicating that PFAS exposure irreversibly impairs key aspects of mitochondrial function. These findings identify cellular targets and mechanisms by which PFAS disrupt female fertility; reveal that PFAS cause intergenerational changes in mammalian embryos; and have important implications for water quality policies.

ALDH2 activation protects against mutant TOMM40-mediated mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.

Decoding the heart-saving power of Sanweidoukou decoction: Mitochondrial and molecular insights.

Skeletal muscle is a vital part of human physiology and is responsible for numerous essential functions. Not surprisingly, the loss of skeletal muscle mass and function is common in several pathologies including atrophy and sarcopenia, which profoundly impact quality of life of those afflicted. Thus, numerous investigations of potential therapies for mitigating or reversing such pathologies are available. Within these studies, experimental cell culture models such as the murine C2C12 myoblasts are commonly used. Over 100 publications have utilized dexamethasone-treated C2C12 myotubes to investigate various aspects of muscle atrophy. The purpose of this systematic review is to describe the experimental conditions common to these experiments, as well as phenotypical myotube presentation, and gene and protein expression of targets that regulate muscle mass, function, and metabolism. A systematic review of literature was conducted until 3 January 2025 using PUBMED. Articles were included if (1) C2C12 myotubes were used, (2) the article included a dexamethasone-only group along with appropriate vehicle or true control and (3) the article assessed at least one of the related phenotypical or molecular outcomes of importance to the scope of the review. A total of 182 articles were included after screening for relevance and inclusion criteria, which were assessed for outcomes (raw data reported when available or using ratio-metric estimates of relative differences between dexamethasone treatment and control). In 24 of 26 unique experiments that utilized 10 μM dexamethasone and 37 of 39 unique experiments that utilized 100 μM dexamethasone, a decrease in myotube diameter was reported (pooled experimental average estimates from 24-h time points 69.8% ± 7.5% and 66.9% ± 14.7% for 10 and 100 μM, respectively, vs. control). All six studies that utilized 10 μM dexamethasone and all nine that treated myotubes with 100 μM dexamethasone reported reduced fusion index (pooled experimental average estimates from 24-h time points: 67.6% ± 5.3% and 68.4% ± 8.4% for 10 and 100 μM, respectively, vs. control). Dexamethasone-treated myotubes also consistently expressed increased atrophic-related molecular targets including Atrogin-1 and muscle atrophy X box1 (MuRF1), as well as reductions in anabolic signalling (specifically, mTORC and Akt activation) and mitochondrial function. The striking consistency of these findings suggests dexamethasone treatment of C2C12 myotubes is a reliable method of mimicking many features common to skeletal muscle pathology. This review provides insight into the use and expected outcomes of the dexamethasone-mediated model of atrophy in C2C12 myotubes and may serve as a helpful reference for future experiments utilizing this model.

MK-3903 alleviates myocardial ischemia/reperfusion injury and mitochondrial dysfunction associated with AMKP-PGC-1α signaling.

Iron dysmetabolism in ovarian follicles: implications for oocyte quality and embryo development in endometriosis.