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Review
. 2021 Sep;58(9):4575-4587.
doi: 10.1007/s12035-021-02412-y. Epub 2021 Jun 10.

Neurological Implications of COVID-19: Role of Redox Imbalance and Mitochondrial Dysfunction

Ravinder K Kaundal  1   2 , Anil K Kalvala  3 , Ashutosh Kumar  4
Affiliations
Review

Neurological Implications of COVID-19: Role of Redox Imbalance and Mitochondrial Dysfunction

Ravinder K Kaundal et al. Mol Neurobiol. 2021 Sep.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 or COVID-19 has been declared as a pandemic disease by the World Health Organization (WHO). Globally, this disease affected 159 million of the population and reported ~ 3.3 million deaths to the current date (May 2021). There is no definitive treatment strategy that has been identified, although this disease has prevailed in its current form for the past 18 months. The main challenges in the (SARS-CoV)-2 infections are in identifying the heterogeneity in viral strains and the plausible mechanisms of viral infection to human tissues. In parallel to the investigations into the patho-mechanism of SARS-CoV-2 infection, understanding the fundamental processes underlying the clinical manifestations of COVID-19 is very crucial for designing effective therapies. Since neurological symptoms are very apparent in COVID-19 infected patients, here, we tried to emphasize the involvement of redox imbalance and subsequent mitochondrial dysfunction in the progression of the COVID-19 infection. It has been articulated that mitochondrial dysfunction is very apparent and also interlinked to neurological symptoms in COVID-19 infection. Overall, this article provides an in-depth overview of redox imbalance and mitochondrial dysfunction involvement in aggravating COVID-19 infection and its probable contribution to the neurological manifestation of the disease.

Keywords: Bioenergetic sensors; COVID-19; Mitochondria; Neurological manifestations; Redox imbalance.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic of the incidence of neurological symptoms and simplified coronavirus replication cycle showing the possible therapeutic _targets with potential repurposed drugs. ACE2, angiotensin-converting enzyme carboxypeptidase 2
Fig. 2
Fig. 2
SARCoV-2 mediated neurological manifestations. ACE2, angiotensin-converting enzyme carboxypeptidase 2
Fig. 3
Fig. 3
Schematic picture showing the plausible mechanism of COVID-19 in mitigating mitochondrial dysfunction. COVID-19 infection stimulates NF-κB pathway and inhibits Nrf2 pathway thereby leads to the redox imbalance and enhances the production of cytokines (TNF-α, IL-1β, IL-6, and IL-10). In turn, TNF-α by acting on its surface receptor enhances the generation of mitochondrial ROS. On another hand, AT1 receptor activation by Ag II formed by ACE involves in regulating AMPK pathway and its downstream mediators controlling mitochondrial function and mitochondrial biogenesis. During the progression of COVID-19 infection, viruses utilize ACE to enter into the host cells and make it unavailable for normal cellular functions, where directly impacts the Ag II homeostasis in controlling cellular functions. This may dysregulate mitochondrial function, perturb mitochondrial biogenesis, and may cause mitochondrial proteotoxicity during COVID-19 infection. Ag II, Angiotensin II; ARE, antioxidant-responsive element; AMPK, adenosine monophosphate–activated protein kinase; Atg, anti-thymocyte globulin; FIP200, FAK family kinase-interacting protein of 200 kDa; GpX, glutathione peroxidase; HIF-1α, hypoxia-inducible factor 1-alpha; HO1, heme oxygenase 1; mTOR, mechanistic _target of rapamycin; NQO1, NAD(P)H dehydrogenase [quinone] 1; SIRT1, silent mating–type information regulation 2 homolog 1; NRF, nuclear respiratory factor; Nrf2, nuclear factor erythroid 2 (NFE2)–related factor 2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Rheb, Ras homolog enriched in the brain; SOD2, superoxide dismutase 2; TFAM, mitochondrial transcription factor; TSC, tuberous sclerosis proteins; Ulk1, unc-51-like autophagy activating kinase; VPS34, vacuolar protein sorting 34
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