Search Results (1,426)

Lipid accumulation disrupts mitochondrial dynamics, leading to dysfunctional energy metabolism and increased oxidative stress. However, the relationship between mitochondrial dynamics and ovarian function in therapeutic contexts is still not fully elucidated. Therefore, the objective of this study was to demonstrate whether increased carnitine palmitoyltransferase 1A (CPT1A) expression induced by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in ovaries of a lipid toxicity-induced rat model by regulating lipid metabolism and mitochondrial dynamics. A rat model of injury was induced through intraperitoneal administration of thioacetamide (TAA) for 12 weeks. During the 8th week of induction, PD-MSCs (2 × 10⁶ cells) were transplanted via the tail vein. Initially, we examined the engraftment of PD-MSCs. The inflammatory response (e.g., IL-6, TNFα) and apoptosis (e.g., LDH levels, TUNEL assay) were significantly increased in the non-transplanted (NTx) group compared to the normal group; however, they were significantly decreased in the transplanted (Tx) group compared to the NTx group (* p < 0.05). Additionally, oxidative stress was attenuated through the regulation of mitochondrial dynamics, including the expression of DRP1, ATP5B, and PGC1α, in the Tx group compared to the NTx group (* p < 0.05). In the NTx group, abnormally accumulated lipid droplets were observed due to dysfunctional mitochondria, whereas in the Tx group, the accumulation of lipid droplets and the expression of CPT1A were significantly comparable to those in the normal group (* p < 0.05). The levels of the steroidogenesis markers (e.g., CYP11A1 and HSD3β1) were decreased in the NTx group compared to the normal group and increased in the Tx group compared to the NTx group (* p < 0.05). The levels of sex hormone and follicular development were protected in the Tx group compared to the NTx group. Furthermore, cocultivation of PD-MSCs with etomoxir (CPT1A inhibitor)-treated primary theca cells increased the expression of steroidogenesis. In conclusion, PD-MSCs improve ovarian function in TAA-induced injury by reducing lipid accumulation and oxidative stress through the regulation of lipid metabolism and mitochondrial dynamics. The upregulation of CPT1A and related mitochondrial proteins contributes to enhanced steroidogenesis and restoration of ovarian homeostasis. These findings offer new insights into the application of stem cell therapies for reproductive medicine. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the gradual and irreversible loss of neurons, especially within the substantia nigra region of the midbrain. Early and accurate diagnosis remains a significant challenge in both research and clinical practice. This difficulty is further compounded by the substantial clinical and molecular heterogeneity of PD, emphasizing the urgent need for reliable biomarkers to enhance diagnostic precision and guide therapeutic strategies. One promising candidate biomarker is cell-free DNA (cfDNA), comprising short DNA fragments composed of mitochondrial (cf-mtDNA) and nucleus-derived (cf-ntDNA) DNA. cfDNA is released into body fluids through physiological or pathological processes such as apoptosis, necrosis, NETosis, or active secretion. The presence of cfDNA in human biological fluids has been utilized for years in oncology and prenatal medicine and, more recently, it has gained attention as a non-invasive diagnostic tool in the context of neurodegenerative diseases such as PD. This review article aims to provide a comprehensive overview of the current knowledge on the origin of cfDNA, highlighting the roles of the mitochondria and cf-mtDNA in PD, mitochondria quality control, and neuroinflammation in cfDNA biogenesis. The review collates available research on cfDNA types in human serum, plasma, and CSF, sequence analysis, and its potential application as a biomarker in the diagnosis and monitoring of PD, contributing to the ongoing search for non-invasive biomarkers of neurodegenerative diseases. Full article

Background: Breast cancer is the most prevalent cancer among women worldwide, and therapeutic resistance represents a major clinical challenge. Mitochondria are key regulators of cancer metabolism, redox homeostasis, and apoptosis, making them potential therapeutic targets. Aim: This study aimed to evaluate the effects of combined Akt and PARP inhibition on mitochondrial metabolic function, energy production, and apoptosis in breast cancer cells. Methodology: The SRB assay was used to compare the viability of MDA-MB-231 and MCF7 cells. A colony formation assay was conducted to assess the capacity of individual cells to develop colonies, and ROS production was quantified using DHR123. Flow cytometric analysis was performed to evaluate cell death, and the Seahorse Mito stress test was used to measure ATP production and essential mitochondrial parameters. Results: The combination of Akt and PARP inhibitors impaired oxidative phosphorylation without inducing a compensatory shift to glycolysis, leading to reduced ATP production, increased ROS generation, and apoptotic cell death in breast cancer cells compared to monotherapy. Conclusions and Recommendations: These findings indicate that the combination of olaparib and capivasterib is a promising therapeutic strategy for breast cancer. Furthermore, evaluation of in vivo toxicity and antitumor effectiveness is essential to validate its potential. Full article

Apoptosis induction in tumor cells is a fundamental therapeutic approach in cancer treatment, with growing interest in plant-derived compounds that offer potent efficacy and reduced toxicity. Cephalotaxus harringtonia, traditionally used in East Asian medicine, contains several bioactive constituents, including homoharringtonine (HHT) and quercetin 3-β-D-glucoside (Q3G), which are known for their anticancer properties. This study investigated the anticancer effects of C. harringtonia leaf extract (CHLE) and its two major compounds, quercetin 3-β-D-glucoside (Q3G) and HHT, against human liver cancer cell lines (HepG2). CHLE exhibited selective cytotoxicity and apoptosis specifically in HepG2 cells while showing minimal toxicity toward normal kidney cells (HK-2). Mechanistic analyses revealed that CHLE induced apoptosis through a mitochondria-mediated intrinsic pathway, characterized by increased reactive oxygen species production, mitochondrial membrane depolarization, and BAX upregulation. These findings demonstrate that C. harringtonia leaf extract possesses potent, selective anticancer activity and may serve as a promising natural candidate for the prevention and therapeutic management of liver cancer. Full article

Background/Objectives: Mitophagy, the selective removal of damaged mitochondria, plays a pivotal role in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy may help mitigate adverse cardiac remodeling. This preclinical study examined the effects of cafestol, a coffee-derived diterpene, on pressure overload-induced cardiac hypertrophy and fibrosis in mice, with emphasis on mitophagy modulation and mitochondrial ultrastructure. Methods: Male normotensive mice underwent transverse aortic constriction (TAC) and received cafestol at 2, 10, or 50 mg/kg/day via oral gavage for 28 days. Cardiac function was assessed by echocardiography. Histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. Protein expression of CD68, CTGF, DDR2, α-SMA, CD44, galectin-3 (Gal3), collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK/ERK, ATF4, p-mTOR/mTOR, and p62 was evaluated. Transmission electron microscopy (TEM) was used to assess autophagosome formation and mitochondrial morphology. Results: TAC induced significant cardiac hypertrophy and fibrosis, accompanied by elevated expression of fibrotic (CTGF, DDR2, α-SMA, collagen I), inflammatory (CD68, CD44, Gal3), apoptotic (Bax, cleaved caspase-3), and endoplasmic reticulum stress markers (GRP78, ATF4). TEM revealed increased autophagosome accumulation and disrupted mitochondrial architecture. Cafestol treatment reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62 levels. TEM findings demonstrated decreased autophagosome burden and preserved mitochondrial structure, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol mitigated pressure overload-induced cardiac remodeling in mice by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. These findings support further investigation of cafestol’s mechanisms and safety profile in preclinical models of cardiovascular disease. Full article

Mitochondria are crucial for energy metabolism and the regulation of apoptosis and the inflammatory response in acute myeloid leukemia (AML). This study examined key mitochondrial characteristics in apoptosis-resistant AML cells during in vitro aseptic pro-inflammatory activation utilizing spectrofluorimetry, quantitative reverse transcription PCR, Western blotting, differential gene expression analysis, flow cytometry, transmission electron microscopy, and cellular respiration analysis. Under conditions of aseptic inflammation simulated in three-dimensional high-density cultures, apoptosis-resistant AML cells exhibited a significant reduction in the transcriptional activity of genes linked to oxidative phosphorylation and the tricarboxylic acid cycle; demonstrated diminished mitochondrial respiration activity; and decreased levels of the mitophagy regulatory proteins PINK1 and Parkin. Furthermore, pathogenic alterations in mitochondrial morphology were observed. These cells demonstrated enhanced intracellular generation of reactive oxygen species, lactate accumulation in the culture media, elevated levels of DRP1 protein, and an increased fraction of small and medium-sized mitochondria. The acquired data demonstrate that aseptic pro-inflammatory activation results in metabolic remodelling of acute myeloid leukemia cells, integrating characteristics of mitochondrial dysfunction. This condition may facilitate the persistence of leukemic cells during inflammatory stress and potentially contribute to the development of an apoptosis-resistant phenotype. The established in vitro model is crucial for examining both the characteristics of energy metabolism and the anti-apoptotic mechanisms in leukemic cells. Full article

GV1001, a multifunctional peptide, has shown numerous biomedical activities, including antioxidant, anti-inflammatory, anti-Alzheimer’s, and anti-atherosclerotic effects, and protects mitochondria from cytotoxic agents. Cisplatin is a widely used chemotherapeutic agent against cancers, but its clinical utility is limited by nephrotoxicity driven by mitochondrial dysfunction in renal epithelial cells. Here, we investigated whether GV1001 protected against cisplatin-induced nephrotoxicity (CIN) in vivo and preserved mitochondrial integrity in human renal epithelial cells in vitro. In mice, GV1001 substantially mitigated CIN by significantly reducing histological damage, kidney injury marker expression, macrophage infiltration, endothelial-to-mesenchymal transition, inflammation, and apoptosis. In cultured renal epithelial cells, GV1001 maintained mitochondrial membrane potential, preserved ATP production, and prevented mitochondrial membrane peroxidation possibly by binding to cardiolipin. GV1001 also reduced the level of reactive oxygen species (ROS), suppressed cytochrome c release into the cytosol, and inhibited activation of apoptosis-related pathways elicited by cisplatin. Collectively, these findings demonstrated that GV1001 might protect kidney from cisplatin through maintaining mitochondrial structure and function and suppressing downstream injury cascades in renal epithelial cells. By directly targeting the mitochondrial mechanisms underlying cisplatin toxicity, GV1001 represents as a promising therapeutic strategy to mitigate CIN and improve the safety of cisplatin-based chemotherapy. Full article

Increasingly unpredictable market demands and the growing market of biosimilars all facilitate lower manufacturing costs. Cell culture media additives have significant potential to improve cell-specific productivity. It has been reported that the treatment of CHO cells with resveratrol results in a reduction in viable cell density and a significant increase in cell-specific productivity. In the present study, we apply our knowledge of resveratrol gained on immortal cell lines to elucidate the details of resveratrol’s effects on mAb-producing CHO cells. In the present study, we confirm that resveratrol causes cell cycle arrest, which results in the increased protein productivity of mAb-producing cells. We demonstrate for the first time that resveratrol induces ER stress in mAb-producing CHO lines, presumably by increasing the amount of specific protein produced. It was found that ER stress did not induce oxidative stress, and cell viability could not be enhanced by apoptosis, necroptosis, or ferroptosis inhibitors. Therefore, these cell deaths may not play a role in the process. We also describe, for the first time, that resveratrol is able to increase ATP levels in mAb-producing CHO cells, thereby providing additional energy to mAb-producing CHO cells. This increased ATP synthesis is likely due to the intensification of respiration, not an increase in the number of mitochondria. Full article

Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a “spatiotemporal-threshold” model for the mitochondrial quality control–cell death axis. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late-stage diagnosis, dense stromal barriers, and resistance to conventional therapies. The tumor microenvironment (TME), marked by hypoxia, aberrant vasculature, and metabolic reprogramming, supports tumor persistence and immune evasion. Targeting metabolic and oxidative vulnerabilities in the TME offers a promising strategy to improve treatment outcomes. This study evaluated the combined effects of photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA), a precursor to the natural photosensitizer protoporphyrin IX (PpIX), and dichloroacetic acid (DCA), a mitochondrial function modulator, in the KRAS-mutated PANC-1 pancreatic cancer cell line. The combination of 5-ALA–PDT and DCA significantly reduced cell viability compared with either treatment alone. Mechanistic analyses revealed activation of multiple regulated cell death pathways, including mitochondria-mediated apoptosis, immunogenic cell death (ICD), and ferroptosis. This was evidenced by increased reactive oxygen species (ROS), loss of mitochondrial membrane potential (ΔΨm), release of danger-associated molecular patterns (DAMPs) such as ATP, and lipid peroxidation. DCA amplified PDT-induced oxidative stress, overcoming redox defenses and enhancing ferroptotic and immunogenic responses. These findings suggest that combining DCA with PDT enhances multimodal cell death in PDAC, providing a rationale for further in vivo studies to validate this redox–metabolic approach to treating chemoresistant pancreatic tumors. Full article

Cancer progression in skeletal muscle (SkM) is very rare, and mechanisms remain unclear. This study assessed the potential of SkM (myocyte)-derived EVs (C2C12-EVs) as anti-cancer agents. Using murine in vitro models, we showed that following treatment with C2C12-EVs, lung carcinoma cells failed to colonise SkM cells, and that C2C12-EVs selectively exerted apoptosis on cancer cells. Uptake of C2C12-EVs by carcinoma cells caused changes in lysosomal function and mitochondrial membrane properties inducing cell death with elevated caspase 3 and 9. The C2C12-EVs also inhibited cell proliferation, affecting cell cycle arrest at S phase and inhibited cell migration. Proteomic analysis of C2C12-EV cargoes highlighted functional enrichment pathways involved in lysozyme function, HIF-1 and PI3K-Akt signalling, regulation of actin cytoskeleton, pyruvate metabolism, platelet activation, and protein processing in ER. Decorin, a muscle cell-specific cytokine released from myocytes in response to stress, was significantly enriched in C2C12-EVs and may contribute to C2C12-EVs’ inhibitory activity on cancer cells. C2C12-EVs may suppress cancer and potentially be used as therapeutic agents for cancer metastasis. Full article

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The search for effective, new antineoplastic drugs with fewer side effects for the treatment of CRC continues, with marine-derived compounds emerging as promising candidates. Objectives: This study investigates the anticancer potential of Frondanol, a nutraceutical derived from the Atlantic Sea cucumber Cucumaria frondosa, known for its potent anti-inflammatory properties. Methods: Two human CRC cell lines, Caco-2 and HT-29, were used to test the effects of Frondanol using various in vitro approaches. Results: Frondanol significantly inhibited cell viability in a dose- and time-dependent manner. At a 1:10,000 dilution, viability decreased to around 30% in Caco-2 and 20% in HT-29 after 24 h, dropping to nearly 5% at 48 h. Furthermore, a clonogenic assay showed around 50% reduction in colony formation in both cell lines. Flow cytometry-based Annexin V staining revealed that Frondanol increased early apoptosis to ~5.2% in Caco-2 and ~9.4% in HT-29 cells, while cell cycle analysis showed accumulation of the sub G0 (apoptotic) phase increasing from 1.5% to 14.7% (Caco-2) and from 1.9% to 23.8% (HT-29). At the molecular level, Frondanol treatment significantly decreased anti-apoptotic protein B-cell lymphoma (Bcl)-2 expression while increasing the expression of the proapoptotic protein Bcl-2-associated X-protein. Additionally, Frondanol markedly induced cytochrome c release from the mitochondria and activated caspase-9, caspase-7, and caspase-3 after treatment, alongside cleavage of the caspase-3 substrate poly (ADP-ribose) polymerase. Frondanol inhibited 5-lipoxygenase activity, further contributing to its anticancer effects. Conclusions: In conclusion, Frondanol inhibits CRC cell proliferation and induces apoptosis through the mitochondrial pathway in vitro, suggesting that it is a potential nutraceutical for the prevention of human colorectal cancer or a valuable source of anticancer compounds. Full article

This review is devoted to research in the field of photodynamic and photothermal therapies for malignant tumors. Special attention in the review is given to photosensitizers based on compounds with a tetrapyrrole ring system, their metal complexes, BODIPY and aza-BODIPY derivatives, squaraines, and photoactivators based on metal complexes with other ligands such as phenanthroline and its derivatives, metronidazole, pyridine, and imidazole derivatives. Additionally, the review considers nanosized carriers for photosensitizers, such as organic and inorganic nanoparticles, liposomes, and extracellular vesicles. This review also discusses the dark toxicity and phototoxicity of these compounds and the processes of free oxygen radical formation, mitochondrial dysfunction, and induction of apoptosis in cancer cells. It has been established that nanoscale delivery systems are more promising for use in photodynamic and photothermal therapy compared to molecular photosensitizers. This is due to their improved solubility in physiological environments, selective accumulation in tumors, prolonged photoactivity, and lower therapeutic dose, which allows for the minimization of the side effects of treatment. Among the molecular photosensitizers under consideration, amphiphilic tetrapyrroles appear to be the most promising. Specifically, tetrapyrrole complexes of indium (III) and iridium (III) with non-porphyrin ligands exhibit favorable photophysical and biological characteristics. The review also indicates that photosensitizers tend to localize in the mitochondria of tumor cells, contributing to oxidative stress and apoptosis activation. This review may be of interest to biochemists and oncologists. Full article

Ovarian cancer (OC) is an aggressive and lethal gynecologic cancer due to its asymptomatic nature resulting in a late diagnosis. OC encompasses distinct histological subtypes, with serous OC representing the most common and aggressive form. However, within the same histological OC subtype, additional heterogeneity has been found in terms of genetic mutations and metabolic profiles probably contributing to treatment response. In cancer, metabolic reprogramming strongly involves mitochondria. Mitochondrial function can be regulated by the cAMP pathway, and its deregulation has been reported in various cancers including OC. Here we analyzed two serous OC cell lines, OC316 and OV56, and eleven human OC tissues. OC316 cell lines showed elevated cAMP level with respect to OV56. The high cAMP levels were associated with activation of thecAMP/PKA/CREB/PGC-1α axis resulting in increased mitochondrial biogenesis, respiratory chain activity, modulation of mitochondrial dynamics and apoptosis resistance. Accordingly, principal component analysis (PCA) of the twenty-three biochemical parameters, in eleven human OC tissues, classified OC into two groups showing different cAMP levels associated with distinct mitochondrial profiles. This analysis highlights a cAMP-dependent stratification revealing two mitochondrial subpopulations within serous OC. These findings indicate that the molecular heterogeneity of OC poses a challenge for understanding disease mechanisms and developing effective targeted therapies. Full article

Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players. Full article