Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

Abstract

SARS-CoV-2 is a positive-strand RNA virus that infects humans through the nasopharyngeal and oral route causing COVID-19. Scientists left no stone unturned to explore a targetable key player in COVID-19 pathogenesis against which therapeutic interventions can be initiated. This article has attempted to review, coordinate and accumulate the most recent observations in support of the hypothesis predicting the altered state of mitochondria concerning mitochondrial redox homeostasis, inflammatory regulations, morphology, bioenergetics and antiviral signalling in SARS-CoV-2 infection. Mitochondria is extremely susceptible to physiological as well as pathological stimuli, including viral infections. Recent studies suggest that SARS-CoV-2 pathogeneses alter mitochondrial integrity, in turn mitochondria modulate cellular response against the infection. SARS-CoV-2 M protein inhibited mitochondrial antiviral signalling (MAVS) protein aggregation in turn hinders innate antiviral response. Viral open reading frames (ORFs) also play an instrumental role in altering mitochondrial regulation of immune response. Notably, ORF-9b and ORF-6 impair MAVS activation. In aged persons, the NLRP3 inflammasome is over-activated due to impaired mitochondrial function, increased mitochondrial reactive oxygen species (mtROS), and/or circulating free mitochondrial DNA, resulting in a hyper-response of classically activated macrophages. This article also tries to understand how mitochondrial fission–fusion dynamics is affected by the virus. This review comprehends the overall mitochondrial attribute in pathogenesis as well as prognosis in patients infected with COVID-19 taking into account pertinent in vitro, pre-clinical and clinical data encompassing subjects with a broad range of severity and morbidity. This endeavour may help in exploring novel non-canonical therapeutic strategies to COVID-19 disease and associated complications.

Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity

“…During infection, the virus hijacks the cellular transcription machinery and mitochondria-suppressing innate immune response to produce viral proteins (Bhowal et al, 2023; Gatti et al, 2020; Shang et al, 2021; Singh et al, 2020). We performed gene ontology (GO) analysis of all differentially expressed genes between SARS-CoV-2 infected and non-infected cells treated with control LNP-mRNA-tdTomato and focused on the top hits in “biological process”, “cellular component” and “KEGG pathway” GO terms to identify the most affected cellular processes, compartments and pathways (Figure 4a).…”

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

“…Patients with SARS-CoV-2 infection displayed depolarized mitochondria and abnormal mitochondrial ultrastructure in monocytes, which was correlated with enhanced inflammatory responses (60). Recently, targeted transcriptome analysis also revealed impairment of mitochondrial OXPHOS and antioxidant gene expression in autopsy samples, which was associated with enhanced HIF-1α stabilization (61,62). Thus, means that can promote mitochondrial metabolic fitness may be promising for developing a novel therapeutic avenue for COVID-19.…”

Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10

“…Interactions between SARS-CoV-2 accessory proteins and host cell mitochondria have been proposed by multiple studies 6,7,17,27 . Morphological changes in shape, size, cristae reorganization and cell location have been shown in mitochondria of SARS-CoV-2infected cells 6,27 .…”

“…In particular, mitochondrion, an organelle which plays an important role in maintenance of multiple metabolic functions, such as energy metabolism and reactive oxygen species (ROS) production, has been recognized as a relevant organelle for the life cycle and cytopathic effects of SARS-CoV-2, as indicated by an enrichment of viral dsRNA signal in mitochondria, coupled with mitochondrial lesions caused by SARS-CoV-2 infection 6, 7 . Furthermore, changes in mitochondrial shape and structure, cristae reorganization and membrane potential disruption have been observed in SARS-CoV-2- infected cells 6 , as well as inhibition of mitophagy with consequent accumulation of damaged mitochondria and augmented stress signaling by inhibiting LC3 binding 7 . By contrast, other study suggests that ORF10 interacts with mitophagy receptor Nip3-like protein X (NIX) and LC3, in turn triggering mitophagy which hinders membrane-anchored anti-viral signaling protein (MAVS)-mediated antiviral signalling 17 .…”