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Brain Research Aug 2024Methamphetamine (MA), a representative amphetamine-type stimulant, is one of the most abused drugs worldwide. Studies have shown that MA-induced neurotoxicity is...
Methamphetamine (MA), a representative amphetamine-type stimulant, is one of the most abused drugs worldwide. Studies have shown that MA-induced neurotoxicity is strongly associated with oxidative stress and apoptosis. While nuclear factor E2-related factor 2 (Nrf2), an antioxidant transcription factor, is known to exert neuroprotective effects, its role in MA-induced dopaminergic neuronal apoptosis remains incompletely understood. In the present study, we explored the effects of MA on the expression levels of Nrf2, dynamin-related protein 1 (Drp1), mitofusin 1 (Mfn1), cytochrome c oxidase (Cyt-c), and cysteine aspartate-specific protease 3 (Caspase 3), as well as the correlations between Nrf2 and mitochondrial dynamics and apoptosis. Brain tissue from MA abusers was collected during autopsy procedures. An MA-dependent rat model was also established by intraperitoneal administration of MA (10 mg/kg daily) for 28 consecutive days, followed by conditioned place preference (CPP) testing. Based on immunohistochemical staining and western blot analysis, the protein expression levels of Nrf2 and Mfn1 showed a decreasing trend, while levels of Drp1, Cyt-c, and Caspase 3 showed an increasing trend in the cerebral prefrontal cortex of both MA abusers and MA-dependent rats. Notably, the expression of Nrf2 was positively associated with the expression of Mfn1, but negatively associated with the expression levels of Drp1, Cyt-c, and Caspase 3. These findings suggest that oxidative stress and mitochondrial fission contribute to neuronal apoptosis, with Nrf2 potentially playing a critical role in MA-induced neurotoxicity.
Topics: Animals; Methamphetamine; Prefrontal Cortex; Mitochondrial Dynamics; Apoptosis; NF-E2-Related Factor 2; Male; Rats; Humans; Adult; Rats, Sprague-Dawley; Neurons; Oxidative Stress; Dynamins; Central Nervous System Stimulants; Amphetamine-Related Disorders; Middle Aged; Young Adult; Female
PubMed: 38685372
DOI: 10.1016/j.brainres.2024.148973 -
Pharmaceutical Research May 2024This study examined the effects of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) on folliculogenesis and mitochondrial dynamics (fission and fusion...
PURPOSE
This study examined the effects of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) on folliculogenesis and mitochondrial dynamics (fission and fusion mechanisms) in ovaries of middle-aged female rats.
METHODS
Experimental groups were young, middle-aged (control), middle-aged + NMN and middle-aged + NR. NMN was administered at a concentration of 500 mg/kg intraperitoneally but NR at a concentration of 200 mg/kg by gavage. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were analyzed by ELISA. Hematoxylin-eosin staining sections were used for histopathological examination and follicles-counting. Expression levels of mitochondrial fission (Drp1, Mff and Fis1) and fusion (Mfn1, Mfn2, Opa1, Fam73a and Fam73b) genes as well as Sirt1 gene were analyzed by RT-PCR. Expression levels of fission-related proteins (DRP1, MFF, FIS1 and SIRT1) were analyzed by Western Blot.
RESULTS
Higher ovarian index, more corpus luteum and antral follicles were detected in NMN and NR groups compared to the control. NMN or NR could rebalance LH/FSH ratio. The control group was determined to possess higher expression levels of fission genes and lower expression levels of fusion genes when compared the young group. In comparison with the control group, both NMN and NR group were found to exhibit less mitochondrial fission but more mitochondrial fussion. Higher gene and protein levels for Sirt1 were measured in NMN and NR groups compared to the control group.
CONCLUSION
This study reveals that NMN alone or NR alone can rebalance mitochondrial dynamics by decreasing excessive fission in middle-aged rat ovaries, thus alleviating mitochondrial stress and correcting aging-induced folliculogenesis abnormalities.
Topics: Animals; Female; Mitochondrial Dynamics; Niacinamide; Ovary; Nicotinamide Mononucleotide; Aging; Rats; Pyridinium Compounds; Sirtuin 1; Luteinizing Hormone; Mitochondrial Proteins; Mitochondria; Ovarian Follicle; Rats, Sprague-Dawley; Follicle Stimulating Hormone; Dynamins
PubMed: 38684562
DOI: 10.1007/s11095-024-03704-3 -
Journal of Cellular and Molecular... May 2024Non-small-cell lung cancer (NSCLC) is a major cause of worldwide cancer death, posing a challenge for effective treatment. Our previous findings showed that Chinese...
Non-small-cell lung cancer (NSCLC) is a major cause of worldwide cancer death, posing a challenge for effective treatment. Our previous findings showed that Chinese herbal medicine (CHM) QiDongNing (QDN) could upregulate the expression of p53 and trigger cell apoptosis in NSCLC. Here, our objective was to investigate the mechanisms of QDN-induced apoptosis enhancement. We chose A549 and NCI-H460 cells for validation in vitro, and LLC cells were applied to form a subcutaneous transplantation tumour model for validation in more depth. Our findings indicated that QDN inhibited multiple biological behaviours, including cell proliferation, cloning, migration, invasion and induction of apoptosis. We further discovered that QDN increased the pro-apoptotic BAX while inhibiting the anti-apoptotic Bcl2. QDN therapy led to a decline in adenosine triphosphate (ATP) and a rise in reactive oxygen species (ROS). Furthermore, QDN elevated the levels of the tumour suppressor p53 and the mitochondrial division factor DRP1 and FIS1, and decreased the mitochondrial fusion molecules MFN1, MFN2, and OPA1. The results were further verified by rescue experiments, the p53 inhibitor Pifithrin-α and the mitochondrial division inhibitor Mdivi1 partially inhibited QDN-induced apoptosis and mitochondrial dysfunction, whereas overexpression of p53 rather increased the efficacy of the therapy. Additionally, QDN inhibited tumour growth with acceptable safety in vivo. In conclusion, QDN induced apoptosis via triggering p53/DRP1-mediated mitochondrial fission in NSCLC cells.
Topics: Animals; Humans; Mice; A549 Cells; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drugs, Chinese Herbal; Dynamins; Lung Neoplasms; Mitochondria; Mitochondrial Dynamics; Reactive Oxygen Species; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 38682742
DOI: 10.1111/jcmm.18353 -
International Journal of Molecular... Apr 2024In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar... (Review)
Review
In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψ) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.
Topics: Mitochondrial Dynamics; Humans; Homeostasis; Animals; Mitochondria; Stress, Physiological; Mitochondrial Proteins; Metalloendopeptidases; Signal Transduction; Autophagy; Dynamins; Apoptosis; GTP Phosphohydrolases
PubMed: 38674151
DOI: 10.3390/ijms25084566 -
International Journal of Molecular... Apr 2024Organ transplantation is associated with various forms of programmed cell death which can accelerate transplant injury and rejection. Targeting cell death in donor...
Organ transplantation is associated with various forms of programmed cell death which can accelerate transplant injury and rejection. Targeting cell death in donor organs may represent a novel strategy for preventing allograft injury. We have previously demonstrated that necroptosis plays a key role in promoting transplant injury. Recently, we have found that mitochondria function is linked to necroptosis. However, it remains unknown how necroptosis signaling pathways regulate mitochondrial function during necroptosis. In this study, we investigated the receptor-interacting protein kinase 3 (RIPK3) mediated mitochondrial dysfunction and necroptosis. We demonstrate that the calmodulin-dependent protein kinase (CaMK) family members CaMK1, 2, and 4 form a complex with RIPK3 in mouse cardiac endothelial cells, to promote trans-phosphorylation during necroptosis. CaMK1 and 4 directly activated the dynamin-related protein-1 (Drp1), while CaMK2 indirectly activated Drp1 via the phosphoglycerate mutase 5 (PGAM5). The inhibition of CaMKs restored mitochondrial function and effectively prevented endothelial cell death. CaMKs inhibition inhibited activation of CaMKs and Drp1, and cell death and heart tissue injury (n = 6/group, < 0.01) in a murine model of cardiac transplantation. Importantly, the inhibition of CaMKs greatly prolonged heart graft survival (n = 8/group, < 0.01). In conclusion, CaMK family members orchestrate cell death in two different pathways and may be potential therapeutic targets in preventing cell death and transplant injury.
Topics: Animals; Mice; Necroptosis; Graft Rejection; Heart Transplantation; Receptor-Interacting Protein Serine-Threonine Kinases; Dynamins; Mitochondria; Endothelial Cells; Male; Mice, Inbred C57BL; Phosphoprotein Phosphatases; Phosphorylation; Calcium-Calmodulin-Dependent Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Signal Transduction
PubMed: 38674016
DOI: 10.3390/ijms25084428 -
Life Science Alliance Jul 2024Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several...
Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.
Topics: Animals; Neural Stem Cells; Mitochondria; Mice; Cell Differentiation; Cell Lineage; Astrocytes; Mitochondrial Dynamics; Oligodendroglia; Neurons; Cells, Cultured; Mitochondrial Proteins; GTP Phosphohydrolases; Neurogenesis; Lateral Ventricles; Dynamins
PubMed: 38664022
DOI: 10.26508/lsa.202302473 -
Cryo-EM structures of membrane-bound dynamin in a post-hydrolysis state primed for membrane fission.Developmental Cell Apr 2024Dynamin assembles as a helical polymer at the neck of budding endocytic vesicles, constricting the underlying membrane as it progresses through the GTPase cycle to...
Dynamin assembles as a helical polymer at the neck of budding endocytic vesicles, constricting the underlying membrane as it progresses through the GTPase cycle to sever vesicles from the plasma membrane. Although atomic models of the dynamin helical polymer bound to guanosine triphosphate (GTP) analogs define earlier stages of membrane constriction, there are no atomic models of the assembled state post-GTP hydrolysis. Here, we used cryo-EM methods to determine atomic structures of the dynamin helical polymer assembled on lipid tubules, akin to necks of budding endocytic vesicles, in a guanosine diphosphate (GDP)-bound, super-constricted state. In this state, dynamin is assembled as a 2-start helix with an inner lumen of 3.4 nm, primed for spontaneous fission. Additionally, by cryo-electron tomography, we trapped dynamin helical assemblies within HeLa cells using the GTPase-defective dynamin K44A mutant and observed diverse dynamin helices, demonstrating that dynamin can accommodate a range of assembled complexes in cells that likely precede membrane fission.
PubMed: 38663399
DOI: 10.1016/j.devcel.2024.04.008 -
Journal of Agricultural and Food... May 2024Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on...
Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on progenitor Leydig cell (PLC) development in prepubertal male rats. Rats were orally administrated DON (0-4 mg/kg) from postnatal days 21-28. DON increased PLC proliferation but inhibited PLC maturation and function, including reducing testosterone levels and downregulating biomarkers like HSD11B1 and INSL3 at ≥2 mg/kg. DON also stimulated mitochondrial fission via upregulating DRP1 and FIS1 protein levels and increased oxidative stress by reducing antioxidant capacity (including NRF2, SOD1, SOD2, and CAT) in PLCs in vivo. In vitro, DON (2-4 μM) inhibited PLC androgen biosynthesis, increased reactive oxygen species production and protein levels of DRP1, FIS1, MFF, and pAMPK, decreased mitochondrial membrane potential and MFN1 protein levels, and caused mitochondrial fragmentation. The mitochondrial fission inhibitor mdivi-1 attenuated DON-induced impairments in PLCs. DON inhibited PLC steroidogenesis, increased oxidative stress, perturbed mitochondrial homeostasis, and impaired maturation. In conclusion, DON disrupts PLC development in prepubertal rats by stimulating mitochondrial fission.
Topics: Animals; Male; Mitochondrial Dynamics; Rats; Leydig Cells; Trichothecenes; Rats, Sprague-Dawley; Oxidative Stress; Mitochondria; Reactive Oxygen Species; Testosterone; Stem Cells; Humans; Dynamins; Membrane Potential, Mitochondrial
PubMed: 38656193
DOI: 10.1021/acs.jafc.4c01151 -
Nutrition & Diabetes Apr 2024The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to...
BACKGROUND
The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to decreased oocyte quality. However, the strategies to improve the oocyte quality and artificial reproductive technology (ART) efficiency of infertile females suffering from diabetes have not been fully studied. In this study, we aimed to examine the effects of nicotinamide mononucleotide (NMN) on oocyte maturation of mouse with type 1 diabetes mouse and explore the underlying mechanisms of NMN's effect.
METHODS
Streptozotocin (STZ) was used to establish the mouse models with type 1 diabetes. The successful establishment of the models was confirmed by the results of body weight test, fasting blood glucose test and haematoxylin and eosin (H&E) staining. The in vitro maturation (IVM) rate of oocytes from diabetic mice was examined. Immunofluorescence staining (IF) was performed to examine the reactive oxygen species (ROS) level, spindle/chromosome structure, mitochondrial function, actin dynamics, DNA damage and histone modification of oocytes, which are potential factors affecting the oocyte quality. The quantitative reverse transcription PCR (RT-qPCR) was used to detect the mRNA levels of Sod1, Opa1, Mfn2, Drp1, Sirt1 and Sirt3 in oocytes.
RESULTS
The NMN supplementation increased the oocyte maturation rate of the mice with diabetes. Furthermore, NMN supplementation improved the oocyte quality by rescuing the actin dynamics, reversing meiotic defects, improving the mitochondrial function, reducing ROS level, suppressing DNA damage and restoring changes in histone modifications of oocytes collected from the mice with diabetes.
CONCLUSION
NMN could improve the maturation rate and quality of oocytes in STZ-induced diabetic mice, which provides a significant clue for the treatment of infertility of the patients with diabetes.
Topics: Animals; Mice; Female; Oocytes; Diabetes Mellitus, Type 1; Diabetes Mellitus, Experimental; Reactive Oxygen Species; Nicotinamide Mononucleotide; Mitochondria; Sirtuin 1; Sirtuin 3; In Vitro Oocyte Maturation Techniques; Superoxide Dismutase-1; DNA Damage; Streptozocin; Oogenesis; Dynamins
PubMed: 38653987
DOI: 10.1038/s41387-024-00280-8 -
Nature Reviews. Molecular Cell Biology Jul 2024
Topics: Endocytosis; Caveolae; Dynamins; Animals; Humans
PubMed: 38649754
DOI: 10.1038/s41580-024-00735-x