scholarly journals SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment

2022 ◽  
Vol 12 ◽  
Author(s):  
Chao Shang ◽  
Zirui Liu ◽  
Yilong Zhu ◽  
Jing Lu ◽  
Chenchen Ge ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Early Stage ◽  
Critical Role ◽  
Fluorescent Microscopy ◽  
Permeability Transition ◽  
Mitochondrial Localization ◽  
Cell Defense ◽  
Mitochondrial Membrane Depolarization

Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.

scholarly journals Mitochondrial Contributions in the Genesis of Delayed Afterdepolarizations in Ventricular Myocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Vikas Pandey ◽  
Lai-Hua Xie ◽  
Zhilin Qu ◽  
Zhen Song
Keyword(s):  
Signaling Pathways ◽  
Energy Demand ◽  
Mitochondrial Permeability Transition ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Depolarization ◽  
Delayed Afterdepolarizations ◽  
Camkii Activation

Mitochondria fulfill the cell’s energy demand and affect the intracellular calcium (Ca2+) dynamics via direct Ca2+ exchange, the redox effect of reactive oxygen species (ROS) on Ca2+ handling proteins, and other signaling pathways. Recent experimental evidence indicates that mitochondrial depolarization promotes arrhythmogenic delayed afterdepolarizations (DADs) in cardiac myocytes. However, the nonlinear interactions among the Ca2+ signaling pathways, ROS, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways make it difficult to reveal the mechanisms. Here, we use a recently developed spatiotemporal ventricular myocyte computer model, which consists of a 3-dimensional network of Ca2+ release units (CRUs) intertwined with mitochondria and integrates mitochondrial Ca2+ signaling and other complex signaling pathways, to study the mitochondrial regulation of DADs. With a systematic investigation of the synergistic or competing factors that affect the occurrence of Ca2+ waves and DADs during mitochondrial depolarization, we find that the direct redox effect of ROS on ryanodine receptors (RyRs) plays a critical role in promoting Ca2+ waves and DADs under the acute effect of mitochondrial depolarization. Furthermore, the upregulation of mitochondrial Ca2+ uniporter can promote DADs through Ca2+-dependent opening of mitochondrial permeability transition pores (mPTPs). Also, due to much slower dynamics than Ca2+ cycling and ROS, oxidized CaMKII activation and the cytosolic ATP do not appear to significantly impact the genesis of DADs during the acute phase of mitochondrial depolarization. However, under chronic conditions, ATP depletion suppresses and enhanced CaMKII activation promotes Ca2+ waves and DADs.

Abstract 3782: β2-Adrenergic Receptor Signaling Positively Modulates Pro-Survival Kinases and Ameliorates Mitochondrial Dysfunction during Doxorubicin Cardiotoxicity

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
Gerald Berry ◽  
Daria Mochly-Rosen ◽  
Daniel Bernstein
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Surface Receptors ◽  
Β2 Adrenergic Receptor ◽  
Improvement In Survival ◽  
Complex I Activity

β2-adrenergic receptors (β2-ARs) modulate cardioprotection through crosstalk with multiple pathways. We have previously shown that β2-ARs are cardioprotective during acute exposure to Doxorubicin (DOX). DOX cardiotoxicity is mediated through a Ca 2+ -dependent opening of the mitochondrial permeability transition pore (MPT) and mitochondrial dysfunction, however the upstream signals linking cell surface receptors and the MPT are not clear. The purpose of this study was to assess crosstalk between β2-AR signaling and mitochondrial function in DOX toxicity. DOX 10 mg/kg was administered to β2−/− and WT mice. Whereas there was no mortality in WT, 85% of β2−/− mice died within 30 min (n=20). Pro- and anti-survival kinases were assessed by immunobloting. At baseline, β2−/− showed normal levels of ϵPKC, but a 16% increase in δPKC compared to WT (p<0.05). After DOX, β2−/− showed a 64% decrease in ϵPKC (p<0.01) and 22% increase in δPKC (p<0.01). The ϵPKC activator ΨϵRACK decreased mortality by 40% in β2−/− mice receiving DOX; there was no improvement in survival with the δPKC inhibitor δV1–1. After DOX, AKT activity was decreased by 76% (p<0.01) in β2−/− but not in WT. The α1-AR blocker prazosin, inhibiting signaling through Gαq, restored AKT activity and reduced DOX mortality by 47%. We next assessed the role of mitochondrial dysfunction in β2−/− mediated DOX toxicity. DOX treated β2−/− mice, but not WT, show marked vacuolization of mitochondrial cristae. Complex I activity decreased 31% in β2−/− mice with DOX; but not in WT. Baseline rate of Ca2+ release and peak [Ca2+]i ratio were increased 85% and 17% respectively in β2−/− myocytes compared to WT. Verapamil decreased mortality by 27% in DOX treated β2−/− mice. Cyclosporine, a blocker of both MPT and calcineurin, reduced DOX mortality to 50%. In contrast, FK506, a blocker of calcineurin but not the MPT, did not reduce DOX mortality. Cyclosporine prevented the decrease in AKT activity in β2−/− whereas FK506 did not. These findings suggest that β2-ARs modulate pro-survival kinases and attenuate mitochondrial dysfunction during DOX cardiotoxicity; absence of β2-ARs enhances DOX toxicity via negative regulation of survival kinases and enhancement of intracellular Ca2+, sensitizing mitochondria to opening of the MPT.

Mitochondrial dysfunction in Parkinson's disease

1999 ◽  
Vol 66 ◽  
pp. 85-97 ◽  
Author(s):  
J.Timothy Greenamyre ◽  
Gillian MacKenzie ◽  
Tsung-I Peng ◽  
Stacy E. Stephans
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nmda Receptor ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Time Course ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Receptor Activation ◽  
Mitochondrial Impairment

The cause of Parkinson's disease (PD) is unknown, but reduced activity of complex I of the electron-transport chain has been implicated in the pathogenesis of both mitochondrial permeability transition pore-induced Parkinsonism and idiopathic PD. We developed a novel model of PD in which chronic, systemic infusion of rotenone, a complex-I inhibitor, selectively kills dopaminergic nerve terminals and causes retrograde degeneration of substantia nigra neurons over a period of months. The distribution of dopaminergic pathology replicates that seen in PD, and the slow time course of neurodegeneration mimics PD more accurately than current models. Our model should enhance our understanding of neurodegeneration in PD. Metabolic impairment depletes ATP, depresses Na+/K(+)-ATPase activity, and causes graded neuronal depolarization. This relieves the voltage-dependent Mg2+ block of the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor, which is highly permeable to Ca2+. Consequently, innocuous levels of glutamate become lethal via secondary excitotoxicity. Mitochondrial impairment also disrupts cellular Ca2+ homoeostasis. Moreover, the facilitation of NMDA-receptor function leads to further mitochondrial dysfunction. To a large part, this occurs because Ca2+ entering neurons through NMDA receptors has 'privileged' access to mitochondria, where it causes free-radical production and mitochondrial depolarization. Thus there may be a feed-forward cycle wherein mitochondrial dysfunction causes NMDA-receptor activation, which leads to further mitochondrial impairment. In this scenario, NMDA-receptor antagonists may be neuroprotective.

scholarly journals Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity

2016 ◽  
Vol 473 (9) ◽  
pp. 1129-1140 ◽  
Author(s):  
Andrew P. Richardson ◽  
Andrew P. Halestrap
Keyword(s):  
Cell Death ◽  
Membrane Proteins ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Molecular Identity ◽  
Permeability Transition Pores

The molecular identity of the mitochondrial permeability transition pore (MPTP), a key player in cell death, remains controversial. Here we use a novel MPTP inhibitor to demonstrate that formation of the pore involves native mitochondrial membrane proteins adopting novel conformations.

Sign in / Sign up

Export Citation Format

Share Document