SARS-CoV-2 and mitochondrial alteration
Since ACE-2 has a clear association with mitochondrial function (Cao et
al., 2019; Shi et al., 2018), SARS-CoV-2 may have an effect on
mitochondrial function as well. ACE-2 knockout mice exhibit impaired
mitochondrial respiration and ATP production, which are compensated by
overexpressing ACE-2 (Shi et al., 2018). Also, genetic variations in
ACE-2 may influence the susceptibility of SARS-CoV-2 and affect
mitochondrial function, as substantial variation in ACE-2 has been
reported around the world (Cao et al., 2020b). Therefore, it is possible
that any specific variation of ACE-2 can modulate mitochondrial function
and make the host especially vulnerable to SARS-CoV-2 infection. As
TMPRSS2 is also responsible for SARS-CoV-2 invasion, the infection may
also alter mitochondrial function through TMPRSS2, which via ERRa
(estrogen-related receptor alpha), may regulate mitochondrial function
(Xu et al., 2018). ERRα is a ligand-independent nuclear receptor that,
together with its coactivator PGC-1α, transcriptionally regulates
mitochondrial (ROS) production, energy homeostasis and mitochondrial
biogenesis (Giguere, 2008; Sonoda et al., 2007). Detailed studies are
warranted to know whether manipulation of mitochondrial function by
SARS-CoV-2 through these receptors influences pathogenesis. There is
recent evidence for this hypothesis that ORF-9b of SARS-CoV-2 is capable
of manipulating mitochondrial function through ACE-2 regulation and the
release of mitochondrial DNA (mtDNA) to suppress host immunity (Shi et
al., 2014). ORF-9b accomplishes this by localizing the viral RNA genome
in the host mitochondria (Shi et al., 2014). The same study showed that
ORF-9b facilitates the degradation of Dynamin-1-like protein (DNML1),
also referred to as dynamin-related protein 1 (Drp1), through
ubiquitination. DNML1 is required for mitochondrial elongation and
fission (Shi et al., 2014), which is an essential process by which
dysfunctional mitochondria are eliminated through mitophagy that
requires for preventing the accumulation of dysfunctional mitochondria,
otherwise may lead to accumulation of dysfunctional mitochondria that
may lead to cell death (Ikeda, Shirakabe, Brady, Zablocki, Ohishi &
Sadoshima, 2015; Lin et al., 2020; Rana et al., 2017; Shirakabe et al.,
2016; Vantaggiato et al., 2019). In addition, ORF-9b also manipulates
the mitochondrial antiviral signaling (MAVS) protein through modulation
of poly (C)-binding protein 2 (PCBP2) and a E3 Ubiquitin Protein Ligase,
AIP4 in a way that degrades MAVS and TNF Receptor Associated Factor
(TRAF) 3 and 6 as well. This may lead to the decreased IFN mediated
antiviral response, allowing the virus to evade the host’s innate
immunity (Shi et al., 2014).
Alongside, SARS-CoV-2’s ORFs7a and 8a may also aid with localization of
the viral genome to the mitochondria, or interact directly or indirectly
with them, and support disease progression (Schaecher, Touchette,
Schriewer, Buller & Pekosz, 2007; Singh, Chaubey, Chen & Suravajhala,
2020; Tan et al., 2007). On the other hand, ORF3a may target
mitochondrial ubiquitin specific peptidase 30 (USP30), a mitochondrial
deubiquitinase involved in mitochondrial homeostasis and mitophagy
control (Freundt, Yu, Park, Lenardo & Xu, 2009). SARS-CoV-2 can control
mitochondrial function through the above mechanisms to help with host
immunosuppression. Similar to other viruses, SARS-CoV-2 can also induce
the Neutrophil extracellular trap (NET)osis mechanism, which is an
inflammatory response that involves mitochondrial biogenesis,
mitochondrial fusion, fission, and mtDNA release to the outside of the
cell (Schonrich & Raftery, 2016; Singh, Chaubey, Chen & Suravajhala,
2020). The release of mtDNA into the cytoplasm triggers the innate
immune response and inflammation, a well-known phenomenon that has been
recently demonstrated (Rongvaux et al., 2014; West et al., 2015; White
et al., 2014). As mtDNA levels increase, the damage and severity of the
illness can progress to multi-organ failure (Aswani et al., 2018). Other
SARS-CoV-2 viral proteins such as ORF9c and Nsp7 were also predicted to
interact with mitochondrial proteins NDUFAF1 and 2, respectively (Singh,
Chaubey, Chen & Suravajhala, 2020). As it is well known that NDUFAF1
and 2 are critical players involved in the assembly of Complex I, such
interaction may augment Complex-I function. This is crucial for the
initiation of electron flow and ROS production, which is required for
proper cellular signaling and immune response (Jin, Wei, Yang, Du &
Wan, 2014; West et al., 2011). The SARS-CoV-2 protein interacts with
mitochondrial proteins that play crucial parts in the mitochondrial
metabolic pathways (Gordon et al., 2020). Other viral interactions of
significance may also include Tom 70, a mitochondrial importer that
plays a critical role in transporting proteins into the mitochondria
and, more importantly, in modulating antiviral cellular defense pathways
(Gordon et al., 2020; Liu, Wei, Shi, Shan & Wang, 2010). Such
interactions provide a means of viral manipulation of the host
mitochondria that suppresses immunity and promotes disease progression
(Figure 3 ). However, a detailed and comprehensive study may
require identifying the crucial mitochondrial proteins targeted by
SARS-CoV-2. Preventing such interactions between SARS-CoV-2 and
mitochondrial proteins during virus establishment is a potential area of
research in identifying potential targets and treatments.