NMN improves high-fat-diet-induced myocardial damage of aging mice through Sirt3/PINK1/Parkin signaling pathway

 Didn't your competent? doctor prescribe NMN years ago? NO? So fucking incompetence reigned and your doctor is still employed?

Editorial: Inflammation in ischemic stroke and novel therapeutic strategies for stroke treatment November 2022 

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NMN improves high-fat-diet-induced myocardial damage of aging mice through Sirt3/PINK1/Parkin signaling pathway

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Abstract

Background

Long-term high-fat diet (HFD) consumption is associated with the development of metabolic cardiomyopathy and contributes to accelerated cardiac aging. Nicotinamide mononucleotide (NMN), a key NAD+ precursor, has shown promise in ameliorating age-related cardiac decline, but its mechanisms are not fully understood.

Methods

14-month-old male C57BL/6J mice were divided into three groups: normal-diet (ND) group, high-fat diet (HFD) group and HFD+NMN group. NMN was added to their drinking water at a dose of 400 mg/kg for 7 months. Cardiac tissues were collected and analyzed using hematoxylin and eosin (H&E) and Masson's trichrome staining, Western blotting, Quantitative Real-Time PCR, and immunohistochemistry. In vitro, H9c2 cardiomyocytes were exposed to palmitic acid (PA) to establish a lipotoxicity model, and the effects of NMN on cell viability and autophagy flux were assessed via MTT assay and mRFP-GFP-LC3 adenoviral transfection.

Results

Compared to HFD group, NMN treatment significantly reduced the heart index, ameliorated myocardial fibrosis, and decreased the expression levels of senescence-associated secretory phenotype (SASP) markers (Serpine1, MMP3, CXCL-1, CXCL-10, P16; P<0.05), as well as senescence markers (P21 and β-gal; P<0.01), pro-inflammatory cytokines (IL-1β and TNF-α; P<0.05) and apoptotic indicators (Bax/Bcl-2 ratio, cleaved caspase-3; P<0.01). Conversely, NMN treatment upregulated the levels of anti-inflammatory factor IL-10 (P<0.01) in the cardiac tissue. Furthermore, NMN treatment increased protein levels of Sirt3, PINK1 and Parkin (P<0.01), and enhanced autophagy-lysosomal markers including LC3-II/LC3-I ratio and TFEB (P<0.05), alongside decreased p62 level (P<0.01) in cardiac tissue. In H9c2 cardiomyocytes, NMN treatment significantly attenuated PA-induced cytotoxicity (P<0.01) and enhanced PA-induced the impaired autophagy flux. Notably, these protective effects were abolished by co-treatment with 3-TYP, a selective Sirt3 inhibitor.

Conclusion

NMN alleviates HFD-induced myocardial damage of aging mice by activating the Sirt3/PINK1/Parkin signaling pathway, enhancing autophagy-lysosomal function. These findings indicate that NMN is a promising therapeutic candidate for the treatment of metabolic cardiomyopathy.

Curcumin Rescues Oxidative Stress-Induced Impairment of PINK1/Parkin Pathway-Mediated Mitophagy in APOE4-Expressing Astrocytes

 Will your competent? doctor and hospital GUARANATEE that human testing occurs? Why not?

Laziness? Incompetence? Or just don't care? NO leadership? NO strategy? Not my job? Not my Problem!

Curcumin Rescues Oxidative Stress-Induced Impairment of PINK1/Parkin Pathway-Mediated Mitophagy in APOE4-Expressing Astrocytes

Jia-Xin Yu 1, Wen-Xuan Zhang 1, Pu-Yu Li 1, Yi-Liang Yang 1 2, Han-Chang Huang 3 4 5

Affiliations 

• PMID: 41706344
 
• DOI: 10.1007/s12035-026-05744-9

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis.

BAP31 represses endoplasmic reticulum stress-mediated apoptosis and alleviates neurodegeneration in Parkinson’s disease

 Your competent? doctor has been working on PINK1 for almost a decade, right! Because of this; Parkinson’s Disease May Have Link to Stroke March 2017 

PINK1 (5 posts to June 2016)

BAP31 represses endoplasmic reticulum stress-mediated apoptosis and alleviates neurodegeneration in Parkinson’s disease

• Yan Qin, 
• Ying Chen, 
• Minghao Chi, 
• Junzhen Jia, 
• Li Wang, 
• Yan Zhao, 
• Zhecheng Wang, 
• Junjun Zhou & 
• Jihong Yao 

Cell Death & Disease volume 16, Article number: 672 (2025) Cite this article

• 507 Accesses

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Abstract

Excessive endoplasmic reticulum (ER) stress and neuronal apoptosis contribute to neurodegeneration in Parkinson’s disease (PD). However, the molecular mechanisms underlying these perturbations and how they are directly regulated remain unclear. B cell receptor-associated protein 31 (BAP31), which is highly expressed in the ER, has been shown to participate mainly in regulating ER stress and apoptosis. Here, our results showed that BAP31 expression was dramatically decreased in PD. Notably, overexpression of BAP31 exerted neuroprotective effects by inhibiting ER stress and apoptosis in vitro and in vivo, whereas BAP31 siRNA strongly abolished these effects. Interestingly, 4-phenylbutyric acid (4-PBA), the ER stress inhibitor, reversed the detrimental effect of BAP31 knockdown in vitro. Mutations in PTEN-induced putative kinase 1 (PINK1) are known to cause autosomal recessive early-onset PD. PINK1 has been implicated in protein phosphorylation pathways that are associated with ER stress and apoptosis. Bioinformatics analysis and our results demonstrated that PINK1 interacts with BAP31 and phosphorylates it at the Ser 142 residue. Furthermore, the protective effects of PINK1 overexpression against ER stress-mediated apoptosis were abolished by BAP31 interference or BAP31-S142A and strengthened by BAP31-S142E. Overall, the present study suggests that BAP31 overexpression exerts neuroprotective effects by inhibiting ER stress-induced apoptosis. Regulation of the PINK1/BAP31 pathway may be a beneficial strategy for PD.

Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation

 Lots of words but NO ACTIONABLE INTERVENTIONS! So useless; you're fired!

Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation

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https://doi.org/10.1016/j.brainresbull.2024.111043

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Under a Creative Commons license

open access

Highlights

• •

  Ginsenoside Rg1 significantly improves cerebral hemorrhagic reperfusion injury.

• •

  Ginsenoside Rg1 attenuates microglial cell inflammatory response.

• •

  Ginsenoside Rg1 reduces mitochondrial autophagy in microglia and inhibits inflammatory vesicle activation.

Abstract

Objective

This study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion.

Methods

In this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments.

Results

In vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats.

Conclusion

Our results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.

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Keywords

Cerebral ischemia/reperfusion injury

Ginsenoside Rg1

Pink1/Parkin

Mitochondrial autophagy

Microglia

1. Introduction

Cerebral ischemia-reperfusion injury (CI/RI) refers to cerebral ischemia that triggers cellular dysfunction and cell death after a specific period, and ischemic tissues are rescued by restoration of blood flow and perfusion. However, reperfusion itself causes tissue damage, which in turn aggravates the degree of cerebral tissue damage (Lim et al., 2021). The complex pathogenesis of CIRI involves multiple components. The early decline in cerebral blood flow causes energy loss and impairs energy synthesis, leading to depolarization of neuronal cell membranes and imbalance of intra- and extracellular ion homeostasis. This can lead to a series of cascade reactions after cerebral ischemia inducing mitochondrial damage, oxidative stress, inflammatory response, Ca²⁺ overload, accelerating neuronal apoptosis, and thus hindering the recovery of neurological function (Zhang et al., 2022). In recent years, research on treating cerebral ischemia-reperfusion injury by regulating mitochondrial autophagy-related molecules has made some progress, which is of positive significance for protecting neurons from ischemia-reperfusion injury and improving patient healing.

As one of the organism's most critical and sensitive organelles, mitochondria plays a crucial role in cell survival (Koch et al., 2017). Among the multiple pathogenesis of cerebral ischemia-reperfusion injury, the mechanism of mitochondrial autophagy plays an important role. Moderate enhancement of mitochondrial autophagy attenuates cerebral ischemia/reperfusion injury, whereas dysfunctional mitochondrial autophagy activates various pathological mechanisms to exacerbate cellular damage (Wu et al., 2021). The Pink1/Parkin pathway is a classical pathway mediating mitochondrial autophagy. Pink1 (PTEN-induced kinase1) senses mitochondrial damage and activates Parkin through phosphorylation and ubiquitination. Activated Parkin constructs a ubiquitin chain on damaged mitochondria and labels them as mitochondria with ubiquitin. Activated Parkin builds ubiquitin chains on damaged mitochondria, tagging them for degradation of damaged mitochondria (Eiyama and Okamoto, 2015, Bingol and Sheng, 2016). Damaged mitochondria releases large amounts of reactive oxygen species, which are involved in the activation of NLRP3 (NLR Family Pyrin Domain Containing 3) inflammatory vesicles, the activation of which further triggers apoptosis and tissue damage. Studies have shown that inhibiting mitochondrial reactive oxygen species production can suppress NLRP3 inflammasome activation (Lin et al., 2019).

Ginsenoside Rg1 (Rg1) is the main active ingredient of ginseng, which can produce significant neuroprotective effects against cerebral ischemic injury through the interaction of different signaling pathways (Xie et al., 2018). Studies have shown that Rg1 can improve ischemic conditions by repairing inflammation associated with dendrites, axons, microglia, and astrocytes, which can significantly reduce apoptosis (Yang et al., 2023, Han et al., 2022a). However, little is known about the mechanism of action of Rg1 in regulating mitochondrial function to inhibit microglia NLRP3 activation to ameliorate cerebral ischemia-reperfusion injury. We utilized aspirin as a positive drug to eliminate the interference of negative results, and set up the FCCP group as a PINK1 activator, and set up the Rg1+CsA group to test whether Rg1 could reverse mitochondrial autophagy caused by CsA. In this study, we observed the changes in mitochondrial morphology and structure as well as the effects on the expression levels of mitochondrial autophagy-related proteins before and after administration of Rg1 in rats with cerebral ischemia-reperfusion model. The possible mechanism of action of Rg1 for the treatment of cerebral ischemia-reperfusion injury was further elucidated by in vivo and in vitro experiments. This will further promote the development of drug candidates to improve cerebral ischemia-reperfusion injury and provide more information and data support for clinical application.

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Deciphering the neuroprotective mechanisms of RACK1 in cerebral ischemia‐reperfusion injury: Pioneering insights into mitochondrial autophagy and the PINK1/Parkin axis

 Something was described here, but further research will be needed to see if any interventions can be created to protect against this neural damage.

Deciphering the neuroprotective mechanisms of RACK1 in cerebral ischemia‐reperfusion injury: Pioneering insights into mitochondrial autophagy and the PINK1/Parkin axis

Lanqing Zhao, ¹ Yu Chen, ² Hongxi Li, ³ Xiaoxu Ding, ² and Jinwei Li ⁴

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Associated Data

Supplementary Materials

Data Availability Statement

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Abstract

Introduction

Cerebral ischemia‐reperfusion injury (CIRI) is a common and debilitating complication of cerebrovascular diseases such as stroke, characterized by mitochondrial dysfunction and cell apoptosis. Unraveling the molecular mechanisms behind these processes is essential for developing effective CIRI treatments. This study investigates the role of RACK1 (receptor for activated C kinase 1) in CIRI and its impact on mitochondrial autophagy.

Methods

We utilized high‐throughput transcriptome sequencing and weighted gene co‐expression network analysis (WGCNA) to identify core genes associated with CIRI. In vitro experiments used human neuroblastoma SK‐N‐SH cells subjected to oxygen and glucose deprivation (OGD) to simulate ischemia, followed by reperfusion (OGD/R). RACK1 knockout cells were created using CRISPR/Cas9 technology, and cell viability, apoptosis, and mitochondrial function were assessed. In vivo experiments involved middle cerebral artery occlusion/reperfusion (MCAO/R) surgery in rats, evaluating neurological function and cell apoptosis.

Results

Our findings revealed that RACK1 expression increases during CIRI and is protective by regulating mitochondrial autophagy through the PINK1/Parkin pathway. In vitro, RACK1 knockout exacerbated cell apoptosis, while overexpression of RACK1 reversed this process, enhancing mitochondrial function. In vivo, RACK1 overexpression reduced cerebral infarct volume and improved neurological deficits. The regulatory role of RACK1 depended on the PINK1/Parkin pathway, with RACK1 knockout inhibiting PINK1 and Parkin expression, while RACK1 overexpression restored them.

Conclusion

This study demonstrates that RACK1 safeguards against neural damage in CIRI by promoting mitochondrial autophagy through the PINK1/Parkin pathway. These findings offer crucial insights into the regulation of mitochondrial autophagy and cell apoptosis by RACK1, providing a promising foundation for future CIRI treatments.

Keywords: cell apoptosis, cerebral ischemia‐reperfusion injury, mitochondrial autophagy, mitochondrial function, neuroprotection, PINK/Parkin pathway, RACK1

This study reveals the key role of RACK1 in CIRI. The study finds that RACK1 regulates mitochondrial function and autophagy. The study confirms the centrality of the PINK1/Parkin pathway. The study offers new strategies for treating CIRI. The study provides comprehensive in vitro and in vivo evidence.

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1. INTRODUCTION

Cerebral ischemic vascular disease ranks as the second leading cause of death in humans. Restoring blood supply to the ischemic area is crucial in treating such diseases; however, reperfusion often leads to secondary brain damage, clinically known as cerebral ischemia‐reperfusion injury (CIRI). ¹ The occurrence of CIRI can result in further damage to the neurocytes in the ischemic area and worsen patients' clinical outcomes. ² Yet, the pathological mechanism of CIRI remains incompletely understood at present. ³ The global incidence of stroke and its concomitant complications, such as CIRI, are on the rise in tandem with the aging global population. These increasing occurrences add significant economic and psychological strain on healthcare infrastructures and the families of affected individuals. ⁴

CIRI involves complex pathological processes, such as energy disruption, intracellular calcium homeostasis loss, and cellular acidosis. ⁵ Recent studies have indicated a close association between CIRI and mitochondrial dysfunction. ⁶ The impairment of mitochondrial function under ischemic conditions leads to an inadequate cellular energy supply, escalating cell death. ⁷ Reperfusion exacerbates this by promoting the generation of oxygen free radicals, further damaging mitochondria and propelling cell apoptosis. ^{8 , 9}

The role of mitophagy, the selective degradation of dysfunctional mitochondria, is receiving increasing focus in the study of CIRI. ¹⁰ This process is critical for removing damaged mitochondria, maintaining cellular function, and proving particularly vital under stress conditions such as ischemia and hypoxia. ^{11 , 12} The PINK1/Parkin pathway is a core player in mitophagy, spearheading the elimination of damaged mitochondria. ¹³

Nonetheless, the molecular intricacies of mitophagy in CIRI are not fully unraveled. RACK1 (receptor for activated C kinase 1) is a multifunctional protein widely distributed within cells, associated with numerous cellular signaling pathways. ^{14 , 15} Additionally, studies have indicated that RACK1 protects against secondary brain injury. ¹⁶ Emerging evidence suggests a potential relationship between RACK1 and mitochondrial autophagy within the context of the PINK1/Parkin pathway. ^{14 , 15 , 17} This study endeavors to intensively explore the functional role of RACK1 in CIRI and its regulatory influence on mitochondrial autophagy. Unveiling these molecular mechanisms can pave the way for identifying innovative targets for CIRI treatment, thereby enhancing patient outcomes and life quality.

In summary, an in‐depth analysis of the role of RACK1 in mitochondrial autophagy within CIRI could unravel novel molecular targets, significantly contributing to the development of advanced therapeutic approaches and positively impacting patient care and prognosis.