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Biology Open Jun 2024Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a...
Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a neurodegenerative phenotype and is known to affect several mitochondrial properties. Therefore, we investigated whether alterations of mitochondrial distribution are involved in Cdk5-associated neurodegeneration. We find that reducing Cdk5 activity does not alter the balance of mitochondrial localization to the somatodendritic vs. axonal neuronal compartments of the mushroom body, the learning and memory center of the Drosophila brain. We do, however, observe changes in mitochondrial distribution at the axon initial segment (AIS), a neuronal compartment located in the proximal axon involved in neuronal polarization and action potential initiation. Specifically, we observe that mitochondria are partially excluded from the AIS in wild-type neurons, but that this exclusion is lost upon reduction of Cdk5 activity, concomitant with the shrinkage of the AIS domain that is known to occur in this condition. This mitochondrial redistribution into the AIS is not likely due to the shortening of the AIS domain itself but rather due to altered Cdk5 activity. Furthermore, mitochondrial redistribution into the AIS is unlikely to be an early driver of neurodegeneration in the context of reduced Cdk5 activity.
PubMed: 38912559
DOI: 10.1242/bio.060335 -
Frontiers in Aging Neuroscience 2024[This corrects the article DOI: 10.3389/fnagi.2017.00409.].
[This corrects the article DOI: 10.3389/fnagi.2017.00409.].
PubMed: 38912525
DOI: 10.3389/fnagi.2024.1419861 -
Heliyon Jun 2024Bazi Bushen capsule (BZBS) is a Chinese herbal compound that is clinically used to treat fatigue and forgetfulness. However, it is still unclear whether and how BZBS...
BACKGROUND
Bazi Bushen capsule (BZBS) is a Chinese herbal compound that is clinically used to treat fatigue and forgetfulness. However, it is still unclear whether and how BZBS affects heart function decline in menopausal women. This study aimed to examine the effect of BZBS on cardiac function in a high-fat diet-fed ovariectomy (HFD-fed OVX) mouse model and elucidate the underlying mechanism of this effect.
METHODS
The experimental animals were divided into five groups: sham group, HFD-fed OVX group, and BZBS (0.7, 1.4, 2.8 g/kg) intervention groups. Senescence β-galactosidase staining and echocardiography were used to evaluate cardiac function. SwissTargetPrediction, KEGG and GO enrichment analyses were used to screen the underlying mechanism of BZBS. The morphological and functional changes in cardiac mitochondria and the underlying molecular mechanism were assessed by transmission electron microscopy, western blotting and biochemical assays. STRING database was used to analysis protein-protein interaction (PPI) network. Molecular docking studies were employed to predict the interactions of specific BZBS compounds with their protein targets.
RESULTS
BZBS treatment ameliorated cardiac senescence and cardiac systole injury in HFD-fed OVX mice. GO and KEGG analyses revealed that the 530 targets of the 14 main components of BZBS were enriched mainly in the oxidative stress-associated pathway, which was confirmed by the finding that BZBS treatment prevented abnormal morphological changes and oxidative stress damage to cardiac mitochondria in HFD-fed OVX mice. Furthermore, the STRING database showed that the targets of BZBS were broadly related to the Sirtuins family. And BZBS upregulated the SIRT3 and elevated the activity of SOD2 in the hearts of HFD-fed OVX mice, which was also verified . Additionally, we revealed that imperatorin and osthole from the BZBS upregulated the expression of SIRT3 by directly docking with the transcription factors HDAC1, HDAC2, and BRD4, which regulate the expression of SIRT3.
CONCLUSION
This research shows that the antioxidative effect and cardioprotective role of BZBS on HFD-fed OVX mice involves an increase in the activity of the SIRT3/SOD2 pathway, and the imperatorin and osthole of BZBS may play central roles in this process.
PubMed: 38912487
DOI: 10.1016/j.heliyon.2024.e32159 -
PeerJ 2024(Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic...
BACKGROUND
(Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of . Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation.
METHODS
The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes.
RESULTS
A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment.
CONCLUSION
Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3/Mcl-1 signaling is potentially involved in this process.
Topics: Gynostemma; Mitophagy; Glycogen Synthase Kinase 3 beta; Signal Transduction; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-akt; Cardiotonic Agents; Plant Extracts; Phosphatidylinositol 3-Kinases; Animals; Rats; Myocytes, Cardiac; Cell Line
PubMed: 38912051
DOI: 10.7717/peerj.17538 -
Annals of Translational Medicine Jun 2024[This corrects the article DOI: 10.21037/atm-21-95.].
[This corrects the article DOI: 10.21037/atm-21-95.].
PubMed: 38911567
DOI: 10.21037/atm-2023-23 -
Cell Death & Disease Jun 2024Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role... (Review)
Review
Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill energy needs for survival and growth, attracting scholarly attention in recent years. Studies indicate that mitochondrial metabolic reprogramming significantly influences the pathophysiological progression of DKD. Alterations in kidney metabolism lead to abnormal expression of signaling molecules and activation of pathways, inducing oxidative stress-related cellular damage, inflammatory responses, apoptosis, and autophagy irregularities, culminating in renal fibrosis and insufficiency. This review delves into the impact of mitochondrial metabolic reprogramming on DKD pathogenesis, emphasizing the regulation of metabolic regulators and downstream signaling pathways. Therapeutic interventions targeting renal metabolic reprogramming can potentially delay DKD progression. The findings underscore the importance of focusing on metabolic reprogramming to develop safer and more effective therapeutic approaches.
Topics: Humans; Diabetic Nephropathies; Mitochondria; Animals; Signal Transduction; Oxidative Stress; Kidney; Metabolic Reprogramming
PubMed: 38910210
DOI: 10.1038/s41419-024-06833-0 -
Scientific Reports Jun 2024Blood-brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine...
Blood-brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1α was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1α expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1α activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1α via regulation of PGC-1α/NLRP3/GSDMD signaling pathway to maintain the integrity of BBB in ischemia/reperfusion injury.
Topics: Animals; Blood-Brain Barrier; Pyroptosis; Mice; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Ischemic Stroke; Endothelial Cells; Benzylisoquinolines; Male; Oxidative Stress; Mitochondria; Mice, Inbred C57BL; Disease Models, Animal; Neuroprotective Agents
PubMed: 38910141
DOI: 10.1038/s41598-024-64815-w -
European Journal of Pharmacology Jun 2024Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is...
Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.
PubMed: 38909934
DOI: 10.1016/j.ejphar.2024.176767 -
Biochimica Et Biophysica Acta.... Jun 2024CHCHD4 (MIA40) is a central component of the mitochondrial disulfide relay system (DRS), is essential and evolutionarily conserved. Previously, we have shown CHCHD4 to... (Review)
Review
CHCHD4 (MIA40) is a central component of the mitochondrial disulfide relay system (DRS), is essential and evolutionarily conserved. Previously, we have shown CHCHD4 to be a critical regulator of tumour cell growth. Here, we use genome-wide CRISPR/Cas9 and SILAC proteomic analyses to delineate mechanisms of CHCHD4 essentiality in cancer. We identify a short-list of common essential genes/proteins associated with CHCHD4 essentiality in tumour cells, which includes subunits of complex I that are known DRS substrates, and genes/proteins involved in key metabolic pathways. Our study highlights a range of nuclear encoded mitochondrial genes essential for CHCHD4-regulated tumour cell growth.
PubMed: 38909850
DOI: 10.1016/j.bbadis.2024.167282 -
Pharmacological Research Jun 2024Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and macrophage... (Review)
Review
Several cardiovascular illnesses are associated with aberrant activation of cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis, and macrophage polarisation as hallmarks contributing to vascular damage and abnormal cardiac function. Meanwhile, these three novel forms of cellular dysfunction are closely related to mitochondrial homeostasis. Mitochondria are the main organelles that supply energy and maintain cellular homeostasis. Mitochondrial stability is maintained through a series of regulatory pathways, such as mitochondrial fission, mitochondrial fusion and mitophagy. Studies have shown that mitochondrial dysfunction (e.g., impaired mitochondrial dynamics and mitophagy) promotes ROS production, leading to oxidative stress, which induces cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage M1 phenotypic polarisation. Therefore, an in-depth knowledge of the dynamic regulation of mitochondria during cellular pyroptosis, ferroptosis, necroptosis, cuproptosis, disulfidptosis and macrophage polarisation is necessary to understand cardiovascular disease development. This paper systematically summarises the impact of changes in mitochondrial dynamics and mitophagy on regulating novel cellular dysfunctions and macrophage polarisation to promote an in-depth understanding of the pathogenesis of cardiovascular diseases and provide corresponding theoretical references for treating cardiovascular diseases.
PubMed: 38909638
DOI: 10.1016/j.phrs.2024.107258