Search

[Display omitted] Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aβ) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides , is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aβ 25-35 -induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aβ 25-35. Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aβ 25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aβ 25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD. [ABSTRACT FROM AUTHOR]

Excessive consumption of fluoride can cause skeletal fluorosis. Mitophagy has been identified as a novel target for bone disorders. Meanwhile, calcium supplementation has shown great potential for mitigating fluoride-related bone damage. Hence, this study aimed to elucidate the association between mitophagy and skeletal fluorosis and the precise mechanisms through which calcium alleviates these injuries. A 100 mg/L sodium fluoride (NaF) exposure model in Parkin knockout (Parkin-/-) mice and a 100 mg/L NaF exposure mouse model with 1% calcium carbonate (CaCO 3) intervention were established in the current study. Fluoride exposure caused the impairment of mitochondria and activation of PTEN-induced putative kinase1 (PINK1)/E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy and mitochondrial apoptosis in the bones, which were restored after blocking Parkin. Additionally, the intervention model showed fluoride-exposed mice exhibited abnormal bone trabecula and mechanical properties. Still, these bone injuries could be effectively attenuated by adding 1% calcium to their diet, which reversed fluoride-activated mitophagy and apoptosis. To summarize, fluoride can activate bone mitophagy through the PINK1/Parkin pathway and mitochondrial apoptosis. Parkin-/- and 1% calcium provide protection against fluoride-induced bone damage. Notably, this study provides theoretical bases for the prevention and therapy of animal and human health and safety caused by environmental fluoride contamination. [Display omitted] • 100 mg/L NaF caused mitochondrial damage and oxidative stress in mouse bones. • 100 mg/L NaF affected bone trabecular growth and bone biomechanical properties. • Inhibition of PINK1/Parkin-mediated mitophagy protected from NaF-induced bone damage. • 1% CaCO 3 supplementation mitigated NaF-induced bone damage via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis. [ABSTRACT FROM AUTHOR]

Dajianzhong decoction (DJZ) is a classical famous formula for treating yang-deficiency-syndrome in traditional Chinese medicine and recorded in Jin-Kui-Yao-Lue in Dynasty of Dong Han. Cognitive aging can present similar features of mitochondrial energy deficits to the clinical features of Yang deficiency. However, there is poor understanding of the effects of DJZ treatment on mitophagy in cognitive aging. The aims of this work were to decipher the effectiveness and mechanism of DJZ against cognitive aging, focusing on mitophagy. YFP-Parkin HeLa cells, D-galactose (D-gal) -induced mice (500 mg/kg for 35 d, s. c.) and SH-SY5Y cells (80 mg/ml for 6 h) were established. Firstly, the formation of YFP-Parkin puncta (a well-known mitophagy marker) in YFP-Parkin HeLa cells was employed to discover the mitophagy induction of DJZ. Moreover, the genes and proteins related to PINK1/Parkin pathway and mitochondrial functions were evaluated after treatment with DJZ in vivo (3.5 g/kg or 1.75 g/kg, i. g, 35 d) and in vitro (0.2, 2 and 20 μg/ml, 12 h). Furthermore, the effectiveness of DJZ (3.5 g/kg or 1.75 g/kg, i. g) for alleviating cognitive aging and nerve damage was measured in D-gal mice. Finally, siPINK1 was applied to reverse validation of DJZ in vitro. The formation of YFP-Parkin puncta in YFP-Parkin HeLa cells was markedly induced by DJZ in a dose-dependent manner. The immunofluorescence intensity of Parkin and the protein expression of Parkin in mitochondrial membrane in D-gal mice were significantly increased after treatment of DJZ. The inhibition of PINK1/Parkin pathway in D-gal-induced mice and SH-SY5Y cells was significantly activated by DJZ. Simultaneously, the impairment of mitochondrial functions induced by D-gal were markedly reversed by DJZ. In addition, DJZ significantly ameliorated the neuropathological injury and cognitive declines in D-gal mice. Finally, after PINK1 was knocked down by siPINK1 in vitro, the neuroprotective effects of DJZ and the Parkin enhancement effect of DJZ were markedly reversed. Our findings firstly showed DJZ could relieve cognitive aging through facilitating PINK1/Parkin-mediated mitophagy to protect against mitochondrial functions, indicating DJZ may be regarded as a promising intervention in cognitive aging. [Display omitted] • Dajianzhong decoction consisting of three herbs improves cognitive performance of aging mice. • Dajianzhong decoction could rescue energy crisis caused by mitochondrial damage. • Dajianzhong decoction targets the PINK1/Parkin pathway to mediate mitochondrial autophagy. [ABSTRACT FROM AUTHOR]

Abstract Background Mitochondrial fission is the essential mechanisms of myocardial ischemia/reperfusion (MI/R)-induced cardiomyocytes apoptosis. Myosin II plays a key role in fission due to the recruitment and actomyosin constriction at the fission site in U2OS cells. However, the role of myosin IIA–actin interaction in regulating MI/R-induced cardiomyocytes mitochondrial fission and apoptosis remains to be fully elucidated. Methods and results When cardiomyocytes are exposed to simulated I/R injury, the myosin IIA protein translocated from the juxtamembrane to the cytoplasm, interacted with actin filaments, formed stress fibers and generated contractile forces. Treatment with the myosin II inhibitor blebbistatin attenuated the myosin IIA–actin complex induced actomyosin contractility and prevented cardiomyocytes apoptosis as reflected by inhibition of cleaved caspase-3 expression, normalization of Bcl-2/Bax levels and decreased apoptotic cells. Meanwhile, blebbistatin inhibited the activation of PINK1/Parkin pathway and ameliorated mitochondrial fission as evidenced by improvement of mitochondrial morphology, inhibition of Drp1 phosphorylation at Ser616 and translocation. Furthermore, CRISPR/Cas9 knockout of myosin IIA blocked I/R-induced apoptosis, suppressed PINK1/Parkin pathway and reduced mitochondrial fission. Importantly, blebbistatin attenuated myocardial apoptosis, inhibited myosin IIA–actin interaction and PINK1/Parkin pathway, suppressed myocardial ultrastructure abnormalities and mitochondrial fission in a mouse MI/R injury model. Conclusions Inhibition of actomyosin contractility induced by myosin IIA–actin interaction could impede myocardial apoptosis and MI/R injury via PINK1/Parkin pathway and mitochondrial fission modulation both in vitro and in vivo , which may be applicable for the development of therapies for cardiovascular diseases. Highlights • Nonmuscle myosin IIA–actin regulates MI/R-induced cardiomyocyte apoptosis. • Nonmuscle myosin IIA–actin modulates MI/R-induced mitochondrial fission. • Myosin IIA-related actomyosin contractility modulates PINK1/Parkin pathway. • Inhibition of myosin IIA–actin interaction attenuates myocardial injury. • Provide new insights on MI/R-induced myocardial apoptosis [ABSTRACT FROM AUTHOR]

Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo . In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic. Our results indicated that Pb activated ATM in vitro and in vivo , and further in vitro studies showed that ATM could co-localize with PINK1 and Parkin in cytosol and interact with PINK1. Knockdown of ATM by siRNA blocked Pb-induced mitophagy even under the circumstance of enhanced accumulation of PINK1 and mitochondrial Parkin. Intriguingly, elevation instead of reduction in phosphorylation level of PINK1 and Parkin was observed in response to ATM knockdown and Pb did not contribute to the further increase of their phosphorylation level, implying that ATM indirectly regulated PINK1/Parkin pathway. These findings reveal a novel mechanism for Pb toxicity and suggest the regulatory importance of ATM in PINK1/Parkin-mediated mitophagy. [ABSTRACT FROM AUTHOR]

• 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]

Functional disorders of mitochondria are closely related to muscle diseases. Many studies have also shown that oxidative stress can stimulate the production of a large number of reactive oxygen species (ROS), which have various adverse effects on mitochondria and can damage muscle cells. In this study, based on our previous research, we focused on the PINK1/Parkin pathway to explore the mechanism by which AS-IV alleviates muscle injury by inhibiting excessive mitophagy. L6 myoblasts were treated with AS-IV after stimulation with hydrogen peroxide (H 2 O 2) and carbonyl cyanide m-chlorophenylhydrazone (CCCP). Then, we detected the related indices of oxidative stress and mitophagy by different methods. A PINK1 knockdown cell line was established by lentiviral infection to obtain further evidence that AS-IV reduces mitochondrial damage through PINK1/Parkin. After mitochondrial damage, the expression of malondialdehyde (MDA) and intracellular ROS in L6 myoblasts significantly increased, while the expression of superoxide dismutase (SOD) and ATP decreased. The mRNA and protein expression levels of Tom20 and Tim23 were decreased, while those of VDAC1 were increased. PINK1, Parkin, and LC3 II mRNA and protein expression increased, and P62 mRNA and protein expression decreased·H 2 O 2 combined with CCCP strongly activated the mitophagy pathway and impaired mitochondrial function. However, abnormal expression of these factors could be reversed after treatment with AS-IV, and excessive mitochondrial autophagy could also be reversed, thus restoring the regulatory function of mitochondria. However, AS-IV-adjusted function was resisted after PINK1 knockdown. AS-IV is a potential drug for myasthenia gravis (MG), and its treatment mechanism is related to mediating mitophagy and restoring mitochondrial function through the PINK1/Parkin pathway. [Display omitted] • The combination of CCCP and H 2 O 2 can induce excessive mitophagy. • AS-IV can reduce excessive mitophagy through the PINK1/Parkin pathway. • AS-IV can improve L6 cells damage and restore mitochondrial function. • The regulatory effect of AS-IV on damaged L6 cells is offset by PINK1 knockdown. [ABSTRACT FROM AUTHOR]

Activation of inflammation is an important pathogenic factor contributing to the development of chronic kidney disease (CKD). Recent studies manifested the implication of impaired mitophagy mediated NLRP3 inflammasome activation in the progression of CKD. Mitochondria-targeted antioxidant mitoTEMPO showed antioxidant and anti-inflammatory properties in kidney disease. This study aims to investigate the protective mechanism of mitoTEMPO on podocyte injury related to mitophagy and NLRP3 inflammasome. Our results showed that mitoTEMPO obviously ameliorated renal function and podocyte injury in CKD model rats induced by cationic bovine serum albumin (C-BSA). More importantly, mitoTMEPO significantly inhibited NLRP3 inflammasome activation compared with CKD model rats (P < 0.01). In vitro , TNF-α damaged human podocyte cells (HPC) and activated NLRP3 inflammasome, which was rescued by NLRP3 inhibitor and mitoTEMPO. Meanwhile, mitoTEMPO lessened excessive mitochondrial ROS (mtROS) and degressive mitochondrial membrane potential (MMP) in HPC. We also found that mitoTEMPO induced mitophagy in vivo and in vitro. Moreover, silenced Parkin dramatically reserved the inhibitory effect of mitoTEMPO on NLRP3 inflammasome. Taking together, these findings reveal that mitoTEMPO ameliorated podocyte injury by inhibiting NLRP3 inflammasome via PINK1/Parkin pathway-mediated mitophagy. MitoTEMPO may be a new candidate to protect against podocyte injury in CKD. [Display omitted] • MitoTEMPO inhibited NLRP3 inflammasome activation to protect podocyte in CKD. • MitoTEMPO improved mitochondrial function by inducing mitophagy in human podocytes. • MitoTEMPO promoted PINK1/Parkin pathway-mediated mitophagy to suppress NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Functional loss of endothelial cells will lead to development and progression of atherosclerosis in diabetic patients. However, dysfunction of endothelial cells in diabetes has yet to be fully understood. We aimed to characterize the potential effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on preventing high glucose-induced endothelial dysfunction and excessive mitophagic response. Pretreatment with liraglutide prevented downregulation of eNOS phosphorylation and NO secretion, and reduced apoptosis and oxidative stress of the human umbilical vein endothelial cells (HUVECs) exposed to high glucose. We further demonstrated that liraglutide likely mediated such protective effects by reducing PINK1/Parkin mediated mitophagy. Liraglutide markedly decreased high glucose-induced mitochondrial ROS, lessened PINK1 expression and mitochondrial accumulation of Parkin, but recovered SIRT1 expression. Seahorse analysis revealed that liraglutide mitigated high glucose-induced reduction of basal and maximum respiration rates as well as spare respiration capacity. Inhibition of Parkin by RNA silencing not only resulted in increased mitochondrial and cytosolic ROS and reduced mitochondrial mass and mitochondrial membrane potential, but also led to increased apoptotic responses in high glucose treated HUVECs which were not preventable by liraglutide. Together, our study reveals that liraglutide acts upstream of the PINK1/Parkin pathway to effectively counteract high glucose induced cell dysfunction by suppression of the PINK1/Parkin-dependent mitophagy. Therefore, its use as an adjunct therapy for type 2 diabetes mellitus is warranted to reduce the risk of atherosclerosis. Further research is required to examine the exact molecules, including SIRT1, upstream of the PINK1/parkin pathway that liraglutide targets to maintain the mitochondrial homeostasis. • Liraglutide improved functionality of HUVECs perturbed by high glucose. • Mitochondrial damage was related to high-glucose exposure which could be preventable by liraglutide. • Liraglutide rescues high glucose-induced PINK1/Parkin-dependent mitophagy. • Liraglutide modulate mitochondrial homeostasis and mitophagic response upstream of PINK1-Parkin pathway. [ABSTRACT FROM AUTHOR]

The purpose of this study was to reveal the therapeutic efficacy and underlying mechanism of cannabinoid type 2 receptor agonist (AM1241) on myocardial ischemia-reperfusion injury (MIRI) in rats. We established a rat myocardial ischemia/reperfusion (I/R) model and H9c2 hypoxia/reoxygenation (H/R) model. ELISA was used to determine the concentrations of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in plasma. EB/TTC staining was performed to observe the myocardial infarct size. Besides, the pathological changes of myocardial tissue were identified via H&E staining and Masson's trichrome staining. TUNEL assay was performed to examine myocardial apoptosis. Then, the protein expression of Pink1, Parkin and autophagy-related markers (Beclin-1, P62 and LC3) were detected by Western blot, and autophagy was evaluated by Mitotracker staining. The results of EB/TTC staining, H&E staining, Masson's trichrome staining and cardiac enzymes measuring showed that AM1241 treatment significantly diminished infarct size, the structural abnormalities and the activities of cardiac enzymes (cTnI, CK-MB, AST and LDH). AM1241 also significantly reduced the number of TUNEL-positive cells induced by I/R in a dose-dependent manner. Furthermore, AM1241 activated Pink1/Parkin signaling pathway and upregulated autophagy level. AM1241 exerts a protective effect against MIRI in rats by inducing autophagy through the activation of Pink1/Parkin pathway. [ABSTRACT FROM AUTHOR]

• THPostC concentration-dependently improved post-ischemic contractile function and reduces the cell death during I/R. • THPostC alleviates mitochondrial dysfunction of cardiomyocytes during simulated I/R. • THPostC activates I/R-induced mitophagy and suppresses mitophagy blocks protective effects of THPostC. • PINK1-Parkin pathway is responsible for THPostC-afforded cardioprotective effects. Triiodothyronine (T 3), the biologically active form of thyroid hormone, was reported to protect myocardium from ischemia/reperfusion (I/R) injury when given before sustained ischemia, but its cardioprotective effects when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact is unknown. Therefore, the present study was designed to determine whether T 3 postconditioning (THPostC) is able to protect the heart from reperfusion injury and its underlying mechanisms. Isolated Sprague-Dawley rat hearts were subjected to 30 min ischemia/45 min reperfusion, triiodothyronine was delivered at the first 5 min of reperfusion. Our data shown that T 3 from 1 to 10 μM during the first 5-min of reperfusion concentration-dependently improved post-ischemic myocardial function. A similar protection was observed in isolated rat cardiomyocytes characterized by the alleviation of I/R-induced loss of mitochondrial membrane potential and exacerbated cell death. Moreover, mitophagy (selectively recognize and remove damaged mitochondria) was significantly stimulated by myocardial I/R, which was enhanced with THPostC. Meanwhile, we found that THPostC stimulated PINK1/Parkin pathway, a critical regulator for mitophagy. Then, adenoviral knockdown of PINK1 and Parkin conformed its roles in the THPostC-mediated cardioprotection. Our results suggest that THPostC confers cardioprotection against I/R injury at least in part by reinforcing PINK1-dependent mitophagy. These findings reveal new roles and mechanisms of triiodothyronine in the cardioprotection against I/R injury. [ABSTRACT FROM AUTHOR]

Presenilin-associated rhomboid-like (PARL), a serine protease located in the inner mitochondrial membrane, has been shown to genetically interact and process PTEN-induced putative kinase a protein known for its critical role in mitochondrial homeostasis and early-onset forms of Parkinson's disease (PD). The identification of a PD-associated variant in the PARL gene (p.Ser77Asn) led us to assess the relevance of PARL for PD pathogenesis using a mutation screening of the coding sequences and adjacent intronic sequences. We investigated 3 single nucleotide polymorphisms (rs3792589, rs13091, and rs3732581), a synonymous base substitution (Leu79Leu) and the previously described p.Ser77Asn mutation, which were subsequently screened in more than 2000 patients and controls. Not detecting the p.Ser77Asn mutation in our cohort, nor a robust association between variations in the PARL gene and PD, the role of disease causing genetic variants in the PARL gene could not be further substantiated in our samples. Our findings indicate that PARL mutations are a rare cause of PD and genetic variants are neither strong nor common risk factors in PD. [ABSTRACT FROM AUTHOR]