Age-related mitochondrial dysfunction as a key factor in COVID-19 disease

Daniel J Moreno Fernández-Ayala, Plácido Navas, Guillermo López-Lluch, Daniel J Moreno Fernández-Ayala, Plácido Navas, Guillermo López-Lluch

Abstract

SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.

Keywords: COVID-19; Cytokine storm; Inflammaging; Inflammation; Mitochondria; Mitochondrial health; Mitochondrial nutrients; Mitochondrial turnover; SARS-CoV-2.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Mitochondrial dysfunction associated with aged mitochondria reduces the efficiency of immune system. The accumulation of mitochondrial damage together with the reduction of the efficiency in the production of energy affects immune system capacity by reducing the capacity to respond to viral infections through a lower release of IFN-I. Aged mitochondria is also involved in the unbalance of immune system by increase of innate response and decrease of the adaptive response found in immunosenescence. Mitochondrial dysfunction releases many damage signals to cytosol that end in the activation of inflammasome and the release of inflammatory cytokines that cause the chronic inflammation associated with aging and age-related diseases.
Fig. 2
Fig. 2
Age-related mitochondrial dysfunction increases the inflammatory response to SARS-CoV-2. The activation of the inflammasome caused by mitochondrial dysfunction during aging and age-related diseases contributes to the chronic inflammation and the release of inflammatory cytokines in the elderly. This system produces a vicious cycle that feed the activity of the inflammasome. When SARS-CoV-2 invades the organism, macrophages showing a high activity of inflammasome can enhance the release of inflammatory cytokines generating the characteristic cytokine storm associated with COVID-19.
Fig. 3
Fig. 3
Essential role of mitochondrial health maintenance in the immune response. Aging and age-related diseases, including many metabolic diseases, aggravate mitochondrial dysfunction and the accumulation of damaged mitochondria in cells including immune cells. The use of prolongevity procedures such as CR, bioactive compounds or physical exercise can reverse this accumulation by inducing mitochondrial turnover and biogenesis. Among these compounds, mito/autophagy inducers, CoQ10 and NAD+ supplementation can help to maintain high levels or healthy mitochondria during aging and avoid immunological unbalance associated with COVID-19 severity.

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