The Role of Autophagy in Sepsis: Protection and Injury to Organs

Yin, Xin; Huang, Xin; Mao, Shuai; Wu, Guang-Ping; Guo, Liheng

doi:10.3389/fphys.2019.01071

Cited by 70 publications

(60 citation statements)

References 88 publications

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“…GFRα1 induces autophagy via activation of the RET/AMPK signalling pathway independently from its interaction with GDNF. In the early stages of sepsis, autophagy is a protective mechanism employed by cells to remove damaged proteins, reduce mitochondrial dysfunction-induced inflammation and eliminate pathogens 102,103 . Furthermore, inhibition of autophagy in mouse models of sepsis results in increased mortality.…”

Section: Vascular Inflammation Autophagy and Cardiovascular Dysfunctionmentioning

confidence: 99%

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Taylor¹,

Das²,

Pearson³

et al. 2020

Preprint

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BACKGROUND Epidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors that impact differential host responses to SARS-CoV-2, resulting in the development of severe COVID-19, is important in gaining greater understanding into the biological mechanisms underpinning life-threatening responses to the virus. These insights could be used in the identification of high-risk individuals and for the development of treatment strategies for these patients. METHODS As of June 6, 2020, there were 976 patients who tested positive for COVID-19 and were hospitalized, indicating they had a severe response to SARS-CoV-2. There were however too few patients with a mild form of COVID-19 to use this cohort as our control population. Instead we used similar control criteria to our previous study looking at shared genetic risk factors between severe COVID-19 and sepsis, selecting controls who had not developed sepsis despite having maximum co-morbidity risk and exposure to sepsis-causing pathogens. RESULTS Using a combinatorial (high-order epistasis) analysis approach, we identified 68 protein-coding genes that were highly associated with severe COVID-19. At the time of analysis, nine of these genes have been linked to differential response to SARS-CoV-2. We also found many novel targets that are involved in key biological pathways associated with the development of severe COVID-19, including production of pro-inflammatory cytokines, endothelial cell dysfunction, lipid droplets, neurodegeneration and viral susceptibility factors. CONCLUSION The variants we found in genes relating to immune response pathways and cytokine production cascades, were in equal proportions across all severe COVID-19 patients, regardless of their co-morbidities. This suggests that such variants are not associated with any specific co-morbidity, but are common amongst patients who develop severe COVID-19. Among the 68 severe COVID-19 risk-associated genes, we found several druggable protein targets and pathways. Nine are targeted by drugs that have reached at least Phase I clinical trials, and a further eight have active chemical starting points for novel drug development. Several of these targets were particularly enriched in specific co-morbidities, providing insights into shared pathological mechanisms underlying both the development of severe COVID-19, ARDS and these predisposing co-morbidities. We can use these insights to identify patients who are at greatest risk of contracting severe COVID-19 and develop targeted therapeutic strategies for them, with the aim of improving disease burden and survival rates.

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Section: Vascular Inflammation Autophagy and Cardiovascular Dysfunctionmentioning

confidence: 99%

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Taylor¹,

Das²,

Pearson³

et al. 2020

Preprint

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“…Depolarization of the MMP due to increased oxidative stress in sepsis is a strong signal to trigger mitophagy [23,24]. Mitophagy is caused by a decrease in MMP that activates the Pink1-Parkin signaling pathway to ubiquitinate autophagy receptors [25,26].…”

Section: Discussionmentioning

confidence: 99%

Pink1/Parkin-mediated mitophagy regulated the apoptosis of dendritic cells in sepsis

Zhang

Luo

Zhong

et al. 2021

Preprint

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Although the Pink1/Parkin-mediated mitophagy is closely related to inflammation and immunoregulation, its effect on apoptosis of splenic dendritic cells (DCs) in sepsis remains unknown. Here, our current study demonstrates that mitophagy is enhanced, and apoptosis of DCs is increased during sepsis in Wild Type (WT) mice. It also shows that mitophagy occurs in the process of the sepsis-induced apoptosis of DCs. Moreover, the level of mitophagy of Pink1-knockout (Pink1-KO) mice is lower than that of WT mice, while the apoptosis of DCs of Pink1-KO mice is increased further more than that of WT mice during sepsis. The mitochondrial dysfunction in DCs is aggravated in Pink1-KO mice during sepsis, which suggests that Pink1/Parkin-mediated mitophagy regulates the apoptosis of DCs by improving mitochondrial function. Thus, an impaired Pink1/Parkin-mediated mitophagy exacerbates the apoptosis of DCs and it might represent a novel therapeutic target to prevent sepsis in the future.

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“…Mitophagy, a form of macroautophagy that selectively degrades damaged mitochondria, is considered as one of the major quality control system of mitochondria, and helps maintaining the integrity and the functions of healthy mitochondria [34]. Mitophagy defect is currently assumed to be an essential pathogenic factor in cancer, neurodegeneration, metabolic disorders, muscle atrophy, inflammation and organ failure caused by sepsis [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Microtubule Defect Involved in ‘Mitophagy Resistance’ Under Subacute Oxidative Stress - Potential Mechanism for Cellular Inflammation

Tamura

Yasuda

Shakuo

et al. 2020

Preprint

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38 [Abstract]39 Introduction: Oxidative stress is considered an essential mechanism in 40 ICU-acquired weakness. The roles of oxidative stress in autophagy/mitophagy 41 dysfunction remains elusive. Microtubule serves as an essential guide rail for 42 auto/mitophagosome trafficking required for proper maturation of 43 auto/mitophagosomes in normal circumstances, and microtubules network 44 formation is regulated by signal transduction mechanisms involving Akt, GSK3β, 45 and the microtubule plus-end tracking molecule, EB1. We have investigated (1) 46 whether oxidative stress affects this pathway, leading to the defective mitophagy 47 response, and (2) whether trehalose, an auto/mitophagy modulator, can 48 ameliorate these pathological conditions. 49 Methods: By stably transfecting markers for auto/mitophagy or MT synthesis, 50 we have established a few new C2C12 myocyte cell lines, expressing, GFP-LC3, 51 EB1-GFP, and/or tandem-fluorescence LC3 (tfLC3). To monitor microtubule 52 network, the cells were stained by SiR-tubulin. The cells were cultured in the 53 presence or absence of oxidative stress by hydrogen peroxide (H2O2) and 54 treated with or without trehalose. The response of mitophagy parameters 55 including vesicle motion and the maturation status was monitored by stimulating 5 56 the cells with carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an 57 established mitophagy inducer, under a time-lapse confocal microscopy. Signal 58 transduction mechanisms linking mitophagy to microtubule formation was 59 analyzed by Western Blotting against Akt and GSK3β.60 Results: Cells under the oxidative stress, showed abolished MT network 61 formation, decreased microtubule synthesis by EB1, and a decrease in 62 CCCP-invoked response of mitophagosome motion, perturbed mitophagosome 63 maturation, and increased superoxide production. Signal resistance of 64 Akt/GSK3β pathway to mitophagic stimulation, was documented. Trehalose 65 treatment reversed signal resistance, diminished MT synthesis, ameliorated the 66 disturbed MT network, and improved maturation defects, suppressing the 67 production of superoxide. 68 Conclusions: Oxidative stress decreases the response of mitophagy and 69 abolishes microtubule network. Trehalose improves the synthetic ability of 70 microtubule and normalized the disturbed microtubule network, resulting in the 71 improvement of the perturbed mitophagosomes maturation under the oxidative 72 stress. 73 6 74 [Keywords] 75 Muscle weakness, ICU-acquired weakness, Autophagy, Mitophagy, Oxidative 76 stress, Microtubule, Akt, GSK3β, Trehalose, Mitochondria 7 77 [Introduction] 78 Muscle wasting and muscle weakness is one of the major complications among 79 many types of critical illnesses including sepsis, burn, and major trauma [1]. In 80 critical illnesses, muscle wasting occurs mostly in chronic phase. More recently, 81 however, ICU-acquired weakness (ICU-AW), which occurs rapidly in the 82 critically ill patients, has acquired both scientific and clinical attention in the field 83 of critical illnes...

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The Role of Autophagy in Sepsis: Protection and Injury to Organs

Cited by 70 publications

References 88 publications

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Analysis of Genetic Host Response Risk Factors in Severe COVID-19 Patients

Pink1/Parkin-mediated mitophagy regulated the apoptosis of dendritic cells in sepsis

Microtubule Defect Involved in ‘Mitophagy Resistance’ Under Subacute Oxidative Stress - Potential Mechanism for Cellular Inflammation

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