Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis

Abstract

Because of the ongoing pandemic around the world, the mechanisms underlying the SARS-CoV-2-induced COVID-19 are subject to intense investigation. Based on available data for the SARS-CoV-1 virus, we suggest how CoV-2 localization of RNA transcripts in mitochondria hijacks the host cell's mitochondrial function to viral advantage. Besides viral RNA transcripts, RNA also localizes to mitochondria. SARS-CoV-2 may manipulate mitochondrial function indirectly, first by ACE2 regulation of mitochondrial function, and once it enters the host cell, open-reading frames (ORFs) such as ORF-9b can directly manipulate mitochondrial function to evade host cell immunity and facilitate virus replication and COVID-19 disease. Manipulations of host mitochondria by viral ORFs can release mitochondrial DNA (mtDNA) in the cytoplasm and activate mtDNA-induced inflammasome and suppress innate and adaptive immunity. We argue that a decline in ACE2 function in aged individuals, coupled with the age-associated decline in mitochondrial functions resulting in chronic metabolic disorders like diabetes or cancer, may make the host more vulnerable to infection and health complications to mortality. These observations suggest that distinct localization of viral RNA and proteins in mitochondria must play essential roles in SARS-CoV-2 pathogenesis. Understanding the mechanisms underlying virus communication with host mitochondria may provide critical insights into COVID-19 pathologies. An investigation into the SARS-CoV-2 hijacking of mitochondria should lead to novel approaches to prevent and treat COVID-19.

Keywords: COVID-19; SARS-CoV; aging; coronavirus; mitochondria; mitochondrial DNA.

Fig. 1.

The most parsimonious structure of major haplotypes present in the angiotensin-converting enzyme carboxypeptidase 2 gene (ACE2). Frequencies of each regional population present in a haplotype are shown in color. Phylogenetic relationships between the observed haplotypes were reconstructed with the NETWORK 5.0 program.

Fig. 2.

Spatial distribution of angiotensin-converting enzyme carboxypeptidase 2 (ACE2) rs2285666 in world populations. Isofrequency maps were generated by using Surfer8 of Golden Software (Golden Software, Inc., Golden, CO), following the Kriging procedure. The isofrequency map illustrates the geographic spread of the respective allele. Data points are shown for each population.

Fig. 3.

A: overview of open-reading frames (ORFs) present in SARS-CoV-1 and SARS-Cov-2. B: the Orf3b gene is absent in CoV-2. E, envelope proteins; M, membrane proteins.

Fig. 4.

Characteristic motif in open-reading frame 3a (Orf3a). A: characteristic LXXC motif in Orf3a from multiple sequence alignment of reported strains. The LWLC is associated with viral expression, whereas CWLC is the motif described in CoV-1. B: conserved CoV-1 sequences of Orf3b. The header of alignment shows the amino acid positions highlighting nonconsensus sequences.

Fig. 5.

Characteristic motif in open-reading frame 7a (Orf7a). A: ADNK motif in Orf7a. B: Orf7b with characteristic LEXQDXX motif with good epitope sites. The header of alignment shows the amino acid positions highlighting nonconsensus sequences.

Fig. 6.

Characteristic motif in open-reading frame 8a (Orf8a). Orf8a shows characteristic CXXE motif as a good epitope site. The header of alignment shows the amino acid positions highlighting nonconsensus sequences.

Fig. 7.

Characteristic motif in open-reading frame 9b (Orf9b). Orf9b shows characteristic DAXX motif as a good epitope site. The header of alignment shows the amino acid positions highlighting nonconsensus sequences.

Fig. 8.

COVID-19-related frequency of occurrence among males and females in significant countries. Data from various countries were obtained from their official sources. These include China (http://www.chinacdc.cn/en/), India (https://www.COVID19india.org/), Iran (behdasht.gov.ir), Australia (www.health.gov.au/COVID-19), the United States (coronavirus.gov), and European countries https://www.ecdc.europa.eu/en/COVID-19/sources-updated).

Fig. 9.

Mechanisms involved in SARS-CoV-2 hijacking of host mitochondria. Schematic showing the SARS-CoV-2 entry into the host cell utilizing angiotensin-converting enzyme carboxypeptidase 2 (ACE2), a polymorphic protein that regulates mitochondrial function. Upon entry into the cells, viral RNA and proteins localize to mitochondria. Postinfection noncoding RNA may also regulate host proteins (such as USP30) involved in mitochondrial dynamics. SARS-2-CoV-2 appears to hijack host mitochondria to suppress host immunity by regulating mitochondrial dynamics, mitochondrial function, and mtDNA release. Hijacking mitochondria may be one of the essential mechanisms leading to COVID-19.