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Ischemia/reperfusion (I/R) is a well-known injury to the myocardium, but the mechanism involved remains elusive. In addition to the well-accepted apoptosis theory, autophagy was recently found to be involved in the process, exerting a dual role as protection in ischemia and detriment in reperfusion. Activation of autophagy is mediated by mitochondrial permeability transition pore (MPTP) opening during reperfusion. In our previous study, we showed that MPTP opening is regulated by VDAC1, a channel protein located in the outer membrane of mitochondria. Thus, upregulation of VDAC1 expression is a possible trigger to cardiomyocyte autophagy via an unclear pathway. Here, we established an anoxia/reoxygenation (A/R) model in vitro to simulate the I/R process in vivo. At the end of A/R treatment, VDAC1, Beclin 1, and LC3-II/I were upregulated, and autophagic vacuoles were increased in cardiomyocytes, which showed a connection of VDAC1 and autophagy development. These variations also led to ROS burst, mitochondrial dysfunction, and aggravated apoptosis. Knockdown of VDAC1 by RNAi could alleviate the above-mentioned cellular damages. Additionally, the expression of PINK1 and Parkin was enhanced after A/R injury. Furthermore, Parkin was recruited to mitochondria from the cytosol, which suggested that the PINK1/Parkin autophagic pathway was activated during A/R. Nevertheless, the PINK1/Parkin pathway was effectively inhibited when VDAC1 was knocked-down. Taken together, the A/R-induced cardiomyocyte injury was mediated by VDAC1 upregulation, which led to cell autophagy via the PINK1/Parkin pathway, and finally aggravated apoptosis., (© 2021 International Federation for Cell Biology.)

Autosomal recessive early-onset Parkinson's disease is most often caused by mutations in the genes encoding the cytosolic E3 ubiquitin ligase Parkin and the mitochondrial serine/threonine kinase PINK1. Studies in Drosophila models and mammalian cells have demonstrated that these proteins regulate various aspects of mitochondrial physiology, including organelle transport, dynamics and turnover. How PINK1 and Parkin orchestrate these processes, and whether they always do so within a common pathway remain to be clarified. We have revisited the role of PINK1 and Parkin in mitochondrial dynamics, and explored its relation to the mitochondrial clearance program controlled by these proteins. We show that PINK1 and Parkin promote Drp1-dependent mitochondrial fission by mechanisms that are at least in part independent. Parkin-mediated mitochondrial fragmentation was abolished by treatments interfering with the calcium/calmodulin/calcineurin signaling pathway, suggesting that it requires dephosphorylation of serine 637 of Drp1. Parkinson's disease-causing mutations with differential impact on mitochondrial morphology and organelle degradation demonstrated that the pro-fission effect of Parkin is not required for efficient mitochondrial clearance. In contrast, the use of Förster energy transfer imaging microscopy revealed that Drp1 and Parkin are co-recruited to mitochondria in proximity of PINK1 following mitochondrial depolarization, indicating spatial coordination between these events in mitochondrial degradation. Our results also hint at a major role of the outer mitochondrial adaptor MiD51 in Drp1 recruitment and Parkin-dependent mitophagy. Altogether, our observations provide new insight into the mechanisms underlying the regulation of mitochondrial dynamics by Parkin and its relation to the mitochondrial clearance program mediated by the PINK1/Parkin pathway., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives such as TP53, PTEN, AKT1, BCL2, BCL2L1, PINK-1, PARKIN, LC3B, and NFE2L2, along with various growth-inducing routes. Our findings demonstrated that TSF effectively repaired the structure of mitochondria in db/db mice. TSF greatly enhanced the mRNA levels of PINK-1. WB and IHC findings indicated that TSF had a notable impact on activating the PINK-1/PARKIN signaling pathway in db/db mice, significantly increasing LC3 and NRF2 expression. Conclusion: Our results indicate that TSF effectively addresses DN by activating the PINK-1/PARKIN signaling pathway and enhancing Mitochondrion structure in experimental diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: This study will be aimed at investigating the effects of Baihu Renshen decoction (BHRS) on type 2 diabetes rats and on macromolecular enzyme 1 (PINK1)/E3 ubiquitin protein ligase (Parkin) pathway. Methods: The experiment was divided into four groups: control group, model group, metformin group and BHRS low-dose group and high-dose group. Forty male rats were selected as samples and randomly assigned to at least one test group. Finally, there are 18 rats in each group. Except for the control group, the rats within the different teams got a high-fat diet associate in nursing an intraperitoneal injection of streptozotocin to make a type 2 diabetes mellitus (T2DM) rat model. The organic chemistry and inflammatory indexes of rats in every cluster were analyzed and compared once four weeks of intragastric administration of comparable reagents to review the therapeutic impact of BHRS on T2DM. In addition, we determined the pathological changes of ductal gland tissue of T2DM rats after treatment, and compared the expression of mitochondrial phagocytosis related proteins in ductal gland tissue of rats in each group. Results: FBG, LDL-C, TC, TG, MDA, IL-1, IL-6, TNF-, and mitophagy-related proteins COXIV, P62, VDAC1, and TOM20 were elevated in the model group compared to the control group, while HDL-C, SOD, GSH-Px, and mitophagy-related proteins PINK1, Parkin, and LC3II/I were decreased (P < 0.05 or P < 0.01). The expressions of FBG, TC, TG, LDL-C, MDA, IL-1, IL-6, TNF-, and mitophagy-related proteins COXIV, P62, VDAC1, and TOM20 were lowered in the BHRS group, while the expressions of HOMA-, HDL-C, SOD, GSH-Px, and mitophagy-related proteins PINK1, Parkin, and LC3II/I were (P < 0.05 or P < 0.01). After therapy with BHRS, hematoxylin-eosin staining showed that the intensity of pancreatic acinar staining increased, and islet cells became clear boundaries that were, regularly arranged, and with reduced vacuoles reduced. Conclusion: BHRS has a clear therapeutic effect on T2DM, which may be achieved by regulating mitochondrial autophagy through the PINK1/Parkin pathway. [ABSTRACT FROM AUTHOR]

Background: Corn peptides, a novel food prepared from corn gluten meal (CGM) by enzymatic hydrolysis or microbial fermentation, have attracted considerable interest owing to their various bioactive properties. However, the underlying mechanism of corn peptides attenuate non-alcoholic fatty liver disease (NAFLD) remains unclear. Objective: This study aimed to investigate the effect of corn peptides in NAFLD and to decipher the underlying mechanisms. Design:NAFLD was induced by a high-fat diet (HFD) for 10 weeks. Corn peptides were administered during the period. Human hepatocellular carcinomas (HepG2) cells induced by free fatty acids were used for this mechanism study. Results: Corn peptides alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, corn peptides blocked mitophagy suppression by HFD based on the increased LC3, ATG7 expressions, as well as decreased P62 levels. Corn peptides increased the expression of proteins involved in fatty acid β-oxidation, such as PPARα and PGC-1α. Corn peptides also improved the Ser/Thr kinase PINK1 (PINK1) and the E3 ubiquitin ligase Parkin (Parkin) translocation to mitochondria, which is confirmed by immunofluorescence. Furthermore, stable knockdown of PINK1 by PINK1 SiRNA in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Conclusion: Corn peptides improved cell injury and ameliorated mitochondrial dysfunction and lipid accumulation via PINK1/Parkin-mediated autophagy in NAFLD. Thus, corn peptides could be a promising nutritional molecule with natural functions for preventing NAFLD. [ABSTRACT FROM AUTHOR]

The accumulation of abnormal aggregation of amyloid-β plaques is one of the most distinguishing pathologies of Alzheimer's disease (AD) and is highly toxic to neurons. Exosomes have demonstrated great potential for AD therapy. However, the impact and underlying mechanism of M2 microglia-derived exosomes (M2-EXOs) in AD progression and outcome are seldom explored. Therefore, we employed an Aβ1-42 oligomer (Aβ)-induced AD model in neuronal HT-22 cells and 7-month-old APP/PS1 mice to investigate the effects of M2-EXOs on AD. We revealed that the AD cell model established by Aβ was accompanied by the upregulation of Aβ1-42, neuronal death, alternation of mitochondrial function and autophagy. M2-EXOs can be internalized by HT-22 cells and MAP2-positive neuronal cells in APP/PS1 mice, and exert neuroprotective functions. Specifically, the administration of M2-EXOs in the AD cell model partially increased cell viability, restored the destruction of mitochondrial membrane potential, and reduced the accumulation of reactive oxygen species inside the mitochondria and cells in a dose-dependent manner. Moreover, we demonstrated that PINK1/Parkin mediated mitophagy was enhanced, while incubation with M2-EXOs decreased beclin1, LC3II, PINK1, and Parkin expression levels. Finally, we observed that compared with APP/PS1 mice treated with PBS, the application of M2-EXOs could decrease Aβ plaque deposition and minus Aβ oligomer expression along with improved PINK1/Parkin pathway-mediated autophagy. Overall, our results imply that M2-EXOs play a protective role in the pathogenesis of AD by ameliorating PINK1/Parkin-mediated mitophagy, indicating that it may provide a novel therapeutic strategy to treat AD. [ABSTRACT FROM AUTHOR]

Objective: Buyinqianzheng Formula (BYQZF) is clinically employed in traditional Chinese medicine to treat Parkinson’s disease (PD) by improving mitochondrial dysfunction. However, the underlying mechanisms by which BYQZF affects mitochondrial morphology remain unknown. Therefore, we observed the effects of BYQZF on mitochondria from the perspective of the PINK1/Parkin pathway. Methods: Cell survival rates were assessed by Cell Counting Kit-8 assay. Expression levels of PINK1 and Parkin mRNA were examined by qRT-PCR. Protein expression levels of PINK1, PINK1-Ser228, Parkin, Parkin-Ser65, Drp1, and Drp1-Ser637 were examined by western blotting. PINK1, Parkin, and MitoTracker® Red CMXRos (MTR) were stained by triple-labeled immunofluorescence, and observed under laser confocal microscopy. Results: Cell survival rate, mitochondrial form factor, mean length and number of mitochondrial network branches, mitochondrial activity, mRNA expression levels of PINK1 and Parkin, and protein expression levels of PINK1, Parkin, and Drp1-Ser637 were reduced after 1-methyl-4-phenylpyridinium (MPP+) intervention. In contrast, Pearson’s correlation coefficients between PINK1 and Parkin, and between Parkin and MTR, as well as protein expression levels of PINK1-Ser228, Parkin-Ser65, and Drp1 increased significantly after MPP+ intervention. Treatment with BYQZF increased cell survival rate, mitochondrial form factor, mean length and number of mitochondrial network branches, mitochondrial activity, mRNA expression levels of PINK1 and Parkin, and expression of PINK1, Parkin, and Drp1-Ser637 proteins. Pearson’s correlation coefficients between PINK1 and Parkin, and between Parkin and MTR, as well as protein expression levels of PINK1-Ser228, Parkin-Ser65, and Drp1 decreased after BYQZF treatment. Conclusion: These results demonstrate that BYQZF has a protective effect on mitochondrial molecular mechanisms in the PD cell model, and the mechanism is related to the PINK1/Parkin pathway.

• Oxytetracycline exposure caused mitochondrial damage and led to oxidative liver damage. • Oxytetracycline inhibited MAPK/Nrf2 pathway mediated enzyme antioxidant system. • Oxytetracycline -induced mitochondrial dynamics imbalance via PINK1/Parkin pathway. • Enzyme-treated soy protein can prevent Oxytetracycline-related oxidative liver damage. Oxytetracycline (OTC), a commonly used tetracycline antibiotic in aquaculture, has been found to cause significant damage to the liver of largemouth bass (Micropterus salmoides). This study revealed that OTC can lead to severe histopathological damage, structural changes at the cellular level, and increased levels of reactive oxygen species (ROS) in M. salmoides. Meanwhile, OTC impairs the activities of antioxidant enzyme (such as T-SOD, CAT, GST, GR) by suppressing the activation of MAPK/Nrf2 pathway. OTC disrupts mitochondrial dynamics and mitophagy through via PINK1/Parkin pathway. The accumulation of damaged mitochondria, combined with the inhibition of the antioxidant enzyme system, contributes to elevated ROS levels and oxidative liver damage in M. salmoides. Further investigations demonstrated that an enzyme-treated soy protein (ETSP) dietary supplement can help maintain mitochondrial dynamic balance by inhibiting the PINK1/Parkin pathway and activate the MAPK/Nrf2 pathway to counteract oxidative damage. In summary, these findings highlight that exposure to OTC disrupts mitochondrial dynamics and inhibits the antioxidant enzyme system, ultimately exacerbating oxidative liver damage in M. salmoides. We propose the use of a dietary supplement as a preventive measure against OTC-related side effects, providing valuable insights into the mechanisms of antibiotic toxicity in aquatic environments. Mechanism for OTC actions on oxidative liver damage of M. salmoides. (A) OTC induces oxidative liver damage. (B) ETSP protects the liver from OTC-related damage [Display omitted]. [ABSTRACT FROM AUTHOR]