Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases

Riya Ganji, P Hemachandra Reddy, Riya Ganji, P Hemachandra Reddy

Abstract

The coronavirus disease 2019 (COVID-19) has become a deadly pandemic with surging mortality rates and no cure. COVID-19 is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) with a range of clinical symptoms, including cough, fever, chills, headache, shortness of breath, difficulty breathing, muscle pain, and a loss of smell or taste. Aged individuals with compromised immunity are highly susceptible to COVID-19 and the likelihood of mortality increases with age and the presence of comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, or chronic obstructive pulmonary disease. Emerging evidence suggests that COVID-19 highjacks mitochondria of immune cells, replicates within mitochondrial structures, and impairs mitochondrial dynamics leading to cell death. Mitochondria are the powerhouses of the cell and are largely involved in maintaining cell immunity, homeostasis, and cell survival/death. Increasing evidence suggests that mitochondria from COVID-19 infected cells are highly vulnerable, and vulnerability increases with age. The purpose of our article is to summarize the role of various age-related comorbidities such as diabetes, obesity, and neurological diseases in increasing mortality rates amongst the elderly with COVID-19. Our article also highlights the interaction between coronavirus and mitochondrial dynamics in immune cells. We also highlight the current treatments, lifestyles, and safety measures that can help protect against COVID-19. Further research is urgently needed to understand the molecular mechanisms between the mitochondrial virus and disease progression in COVID-19 patients.

Keywords: Alzheimer’s disease; COVID-19; SARS-CoV-2; diabetes; immune response; lifestyle; mitochondrial dynamics; obesity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Ganji and Reddy.

Figures

Figure 1
Figure 1
Structure of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2; Vallamkondu et al., 2020).
Figure 2
Figure 2
SARS-CoV-2 entry into host cells in the lung. Spike glycoproteins on the SARS-CoV-2 particle attach to human angiotensin-converting enzyme-2 for entry (Hoffmann et al., 2020). Host transmembrane serine protease 2 primes the spike protein for attachment (Hoffmann et al., 2020). Virus particle enters through endocytosis and spike proteins are cleaved (Ou et al., 2020).
Figure 3
Figure 3
SARS-CoV-2 products localize to the mitochondria inside human host cells. SARS-CoV-2 RNA genome has been shown to localize in the mitochondrial matrix through an unknown mechanism. Viral protein ORF-9b interacts with translocase of outer mitochondrial membrane-70 (TOMM70), a host receptor that may affect activation of the interferon response (Gordon et al., 2020). Viral ORF-7a localizes to transmembrane protein Bcl-xL on the OMM, causing the promotion of apoptosis (Schaecher et al., 2007). Viral ORF-3a is theorized to localize to ubiquitin-specific protease-30 (USP30), which is typically involved in mitochondrial fission/fusion and mitophagy; and the sequence of ORF-3a that interacts with USP30 has been found in SARS-CoV-2 (Singh et al., 2020).
Figure 4
Figure 4
Functions of normal mitochondria vs. effects on mitochondria in the presence of SARS-CoV-2. Normal mitochondria have a balance on fission and fusion, produce ROS only in quantities necessary, have balanced iron storage, and use mitophagy to upkeep functional mitochondria and protect the cell against damage. In the presence of SARS-CoV-2, mitochondria may have increased fusion (Shi et al., ; Zhang et al., 2020), an excess of ROS production (Kuka et al., ; Kang et al., 2016), too much iron in storage (Saleh et al., 2020), and impaired mitophagy that leads to platelet apoptosis (Lee et al., ; Tang et al., 2020). SARS-CoV-2 affects mitochondria may also serve as a source of double-membraned vesicles for the virus to travel in (Singh et al., 2020).
Figure 5
Figure 5
Proposed treatments for targeting mitochondrial-centered dysfunction in COVID-19. Encouraging mitophagy with Urolithin A (found in pomegranate juice; Ryu et al., 2016), calorie restriction (Khraiwesh et al., 2014), and polyamine spermidine (Eisenberg et al., 2016) may reduce severe effects of COVID-19. Mitochondrial transfer (Islam et al., 2012) may protect against acute lung injury. Exercise, breathing exercises, and foods high in anti-oxidants and with anti-inflammatory properties are lifestyle changes that can contribute to better protection against the severe respiratory symptoms in COVID-19.

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