Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications

Abstract

Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca²⁺ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.

Keywords: CoV; Mitochondria; Mitochondrial localization signal; ROS; SARS; Virus.

Fig. 1

Illustration demonstrating the effect of SARS-CoV infection on mitochondrial structure and function. Host cell interferon (IFN) response to virus infection: ORF-9b degrades DRP1 leading to mitochondrial fusion and host cell interferon (IFN) response to virus infection. Changes in mtDNA copy number: SARS-CoV proteins can influence ROS level, perturbation of Ca2 + signaling, changes in mtDNA copy number. Apoptosis: ORF9b degrades MAVS, TRAF3 and TRAF6 induce structural and functional change resulting in apoptosis.

Fig. 2

Signal peptide cleavage sites in SARS-CoV2 peptides. A) spike protein with a probability score of 0.968. B) ORF7a protein with a probability score of 0.998. C) ORF8 protein with a probability score of 0.997. D) ORF10 protein with a probability score of 0.262.