The SARS-CoV-2 spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice

Cao, Xiaoling; Nguyen, Vi; Tsai, Joseph C.; Gao, Chao; Tian, Yan; Zhang, Yuping; Carver, Wayne; Kiaris, Hippokratis; Cui, Taixing; Tan, Wenbin

doi:10.1016/j.molmet.2023.101756

Cited by 9 publications

(7 citation statements)

References 64 publications

(81 reference statements)

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“…Avolio et al [ 101 ] found the free SARS-CoV-2 spike protein, separated from the virus, could cause microvascular disease via several mechanisms, which include stimulation of cardiac pericytes to engage in pro-inflammatory cytokine production via CD147 receptor binding. Further evidence for the pathogenicity of spike protein is from mouse studies where spike protein-induced cardiac fibrosis and myocardial contractile impairment may underlie COVID-19-related cardiomyopathy [ 102 ].…”

Section: Evidence Of ‘Spikeopathy’—spike Protein Pathogenicitymentioning

confidence: 99%

‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

Parry,

Lefringhausen,

Turni

et al. 2023

Biomedicines

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The COVID-19 pandemic caused much illness, many deaths, and profound disruption to society. The production of ‘safe and effective’ vaccines was a key public health target. Sadly, unprecedented high rates of adverse events have overshadowed the benefits. This two-part narrative review presents evidence for the widespread harms of novel product COVID-19 mRNA and adenovectorDNA vaccines and is novel in attempting to provide a thorough overview of harms arising from the new technology in vaccines that relied on human cells producing a foreign antigen that has evidence of pathogenicity. This first paper explores peer-reviewed data counter to the ‘safe and effective’ narrative attached to these new technologies. Spike protein pathogenicity, termed ‘spikeopathy’, whether from the SARS-CoV-2 virus or produced by vaccine gene codes, akin to a ‘synthetic virus’, is increasingly understood in terms of molecular biology and pathophysiology. Pharmacokinetic transfection through body tissues distant from the injection site by lipid-nanoparticles or viral-vector carriers means that ‘spikeopathy’ can affect many organs. The inflammatory properties of the nanoparticles used to ferry mRNA; N1-methylpseudouridine employed to prolong synthetic mRNA function; the widespread biodistribution of the mRNA and DNA codes and translated spike proteins, and autoimmunity via human production of foreign proteins, contribute to harmful effects. This paper reviews autoimmune, cardiovascular, neurological, potential oncological effects, and autopsy evidence for spikeopathy. With many gene-based therapeutic technologies planned, a re-evaluation is necessary and timely.

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Section: Evidence Of ‘Spikeopathy’—spike Protein Pathogenicitymentioning

confidence: 99%

‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

Parry,

Lefringhausen,

Turni

et al. 2023

Biomedicines

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“…Recently, Wang et al and Wu et al reported that S1 aggregates α-Syn via mitochondrial damage and Ser129 phosphorylation [ 30 , 31 ]. However, both studies have limitations in proving this hypothesis, as they used a single neuronal cell line and the experiments involved artificial overexpression of both S1 and α-Syn, which fails to reflect the systemic environment and transmembrane dynamics of circulating S1 in an actual brain.…”

Section: Discussionmentioning

confidence: 99%

“…The imbalance between the mutual regulation of mitochondria and α-synuclein leads to neuronal damage and contributes to the development of α-synucleinopathy [ 28 ]. S1 has been reported to cause mitochondrial dysfunction, altering Δψm, mCa2+ overload, reactive oxygen species (ROS) accumulation, and mitochondrial dynamics in human cell lines and rodent models [ 29 , 30 , 31 ]. Reports also indicate that S1 aggregates α-Syn directly via induction of mitochondrial ROS in neuronal cell lines [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin

Chang,

Park,

Lee

et al. 2024

Biomedicines

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Abnormal aggregation of α-synuclein is the hallmark of neurodegenerative diseases, classified as α-synucleinopathies, primarily occurring sporadically. Their onset is associated with an interaction between genetic susceptibility and environmental factors such as neurotoxins, oxidative stress, inflammation, and viral infections. Recently, evidence has suggested an association between neurological complications in long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’) and α-synucleinopathies, but its underlying mechanisms are not completely understood. In this study, we first showed that SARS-CoV-2 Spike protein 1 (S1) induces α-synuclein aggregation associated with activation of microglial cells in the rodent model. In vitro, we demonstrated that S1 increases aggregation of α-synuclein in BE(2)M-17 dopaminergic neurons via BV-2 microglia-mediated inflammatory responses. We also identified that S1 directly affects aggregation of α-synuclein in dopaminergic neurons through increasing mitochondrial ROS, though only under conditions of sufficient α-Syn accumulation. In addition, we observed a synergistic effect between S1 and the neurotoxin MPP+ S1 treatment. Combined with a low dose of MPP+, it boosted α-synuclein aggregation and mitochondrial ROS production compared to S1 or the MPP+ treatment group. Furthermore, we evaluated the therapeutic effects of metformin. The treatment of metformin suppressed the S1-induced inflammatory response and α-synucleinopathy. Our findings demonstrate that S1 promotes α-synucleinopathy via both microglia-mediated inflammation and mitochondrial ROS, and they provide pathological insights, as well as a foundation for the clinical management of α-synucleinopathies and the onset of neurological symptoms after the COVID-19 outbreak.

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“…In an autopsy study of deceased patients with COVID-19, Jum'ah et al [40] have found that increased macrophage density correlates with the degree of necrosis of cardiomyocytes. Cao et al [22] have found that invasive cellular S proteins induce long-term transcriptional repression of mitochondrial metabolism-associated genes in cardiomyocytes, thus leading to cardiac fibrosis, diminished myocardial contractility, and eventually myocardial injury. These observations suggest that SARS-CoV-2 can infect human cardiomyocytes and consequently lead to direct cardiomyocyte death and myocardial inflammation.…”

Section: Sars-cov-2 Causes Direct Myocardial Injury Via Ace2mentioning

confidence: 99%

Possible Mechanisms of SARS-CoV2-Mediated Myocardial Injury

Yu¹,

Wu²,

Song³

et al. 2023

CVIA

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly become a global health emergency. In addition to causing respiratory effects, SARS-CoV-2 can result in cardiac involvement leading to myocardial damage, which is increasingly being explored in the literature. Myocardial injury is an important pathogenic feature of COVID-19. The angiotensin-converting enzyme-2 receptor plays a key role in the pathogenesis of the virus, serving as a “bridge” allowing SARS-CoV-2 to invade the body. However, the exact mechanism underlying how SARS-CoV-2 causes myocardial injury remains unclear. This review summarizes the main possible mechanisms of myocardial injury in patients with COVID-19, including direct myocardial cell injury, microvascular dysfunction, cytokine responses and systemic inflammation, hypoxemia, stress responses, and drug-induced myocardial injury. Understanding of the underlying mechanisms would aid in proper identification and treatment of myocardial injury in patients with COVID-19.

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The SARS-CoV-2 spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice

Cited by 9 publications

References 64 publications

‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

SARS-CoV-2 Spike Protein 1 Causes Aggregation of α-Synuclein via Microglia-Induced Inflammation and Production of Mitochondrial ROS: Potential Therapeutic Applications of Metformin

Possible Mechanisms of SARS-CoV2-Mediated Myocardial Injury

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