Research
Viral Targeting of Mitochondria May Alter Cognition and Enhance Viral Transmission
by George B. Stefano1
1Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic
Cite as: Stefano, G. B. (2024). Viral Targeting of Mitochondria May Alter Cognition and Enhance Viral Transmission. THE MIND Bulletin on Mind-Body Medicine Research, 4, 5-9. https://doi.org/10.61936/themind/202406043
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While several recent studies highlighted the acute and chronic changes resulting from infection with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) (Wang, Kream and Stefano, 2020; Chen et al., 2020; Pezzini and Padovani, 2020), the long-term effects of COVID-19 on the CNS remain largely unknown (Wang, Kream and Stefano, 2020). The results of several recent studies revealed that SARS-CoV-2 infection can lead to altered cognitive function and neuropsychiatric and developmental disorders, including depression and autism, respectively (Lau et al., 2004; Tsai et al., 2004; Correa-Palacio et al., 2020; Chandra et al., 2020; Mawhinney et al., 2020; Beach et al., 2020; Epstein et al., 2020; Chen et al., 2020; Zhang and Ma, 2020; Ptáček et al., 2020). The psychological symptoms, behavioral changes, cognitive impairment, confusion, and poor concentration resulting from SARS-CoV-2 infection are components of a characteristic “brain fog” (Croall et al., 2020).
The degree of initial lung damage resulting from an acute SARS-CoV-2 infection has an impact on the long-term effects of infection and may lead to both acute and chronic changes in the central nervous system (CNS) (Calabrese et al., 2020; Tian et al., 2020; Xu et al., 2020). Findings from recent modeling studies suggest that both genomic and subgenomic RNA SARS-CoV-2 transcripts can hijack the host cell by targeting the nucleolus and the mitochondrial matrix (Wu et al., 2020). Specifically, the SARS-CoV-2 pathogen may integrate components of its genome into the mitochondrial matrix of the host cell, thereby impairing mitochondrial energy metabolism by reducing the availability and utilization of oxygen (Wu et al., 2020; Shenoy, 2020; Singh et al., 2020). This viral-mitochondrial interaction results in enhanced energy use, a reduction in available mitochondrial energy, and reduced immune responses by the host cell, thereby promoting virus replication and survival (Shenoy, 2020; Singh et al., 2020; Stefano, Esch and Kream, 2020; Ptáček et al., 2020). These pathological effects may lead to some of the long-term cognitive, psychiatric, and neurodegenerative sequelae of this infection (Ptáček et al., 2020).
The mechanisms used by SARS-CoV-2 to alter host cell mitochondrial function and energy metabolism may lead to the development of impaired cognitive function. Cellular mitochondria evolved from an alphaproteobacterial-like bacterial ancestor and have retained the ability to move between cells and toward hypoxic microenvironments and to exist extracellularly, for example, in the cerebrospinal fluid (Stefano, Esch and Kream, 2020; Stefano, Esch and Kream, 2019; Hayakawa et al., 2018; Nakamura, Park and Hayakawa, 2020). In our previous studies, it was suggested that mitochondrial targeting may be an initial step in the cellular stress response to infection and similar perturbations given their unique oxygen-sensitive functions that are critical factors initiating protective proinflammatory reactions (Esch et al., 2020).
Physiological stress resulting from inflammation can increase one’s susceptibility to viral infection; furthermore, several neurological disorders have been linked to chronic inflammation. (Esch and Stefano, 2002; Esch et al., 2002). Certain viruses, for example, human immunodeficiency virus can enter the CNS by hijacking immune cells to facilitate penetration through the blood-brain barrier (BBB) (Stefano et al., 2021; Stefano et al., 2022). Thus, normal cell trafficking through the BBB can introduce pathogens into the CNS, which occurs at higher frequency in activated immune cells, further implying the susceptibility of the BBB and questioning its’ barrier nature.
These virus pathogens can utilize complementary conformational shape matching to target mitochondria and perturb pathways leading to energy production, thereby altering cognition, because of its constant need for high levels of energy to function (Stefano et al., 2021; Stefano et al., 2022). Of note, mitochondria may represent the ideal target for these viruses because of their bacterial origin; this permits the viruses to replicate their evolutionarily ancient interactions (Stefano and Kream, 2022; Stefano et al., 2022; Büttiker et al., 2023; Stefano et al., 2023). Overall, virus-mediated impairment of mitochondrial function and cognition may lead to alterations in both cognitive and noncognitive protective behaviors that lead to increased infectivity and transmission (Stefano et al., 2021).
SARS-CoV-2 infection may also lead to mitochondrial synchronization in multiple cells (Esch et al., 2002; Tobin, Laghi and Jubran, 2020; Huang et al., 2018). Furthermore, if energy metabolism is compromised, the resulting immune dysfunction will increase the spread of the virus both within and ultimately between individuals. Because neural tissue requires high oxygen levels to function optimally, mitochondrial dysfunction resulting from SARS-CoV-2 infection may lead to one or more COVID-19-associated neurological sequelae (Esch and Stefano, 2002; Esch et al., 2002). Therefore, the development of “brain fog” as an outcome of SARS-CoV-2 infection may be the result of a conserved strategic mechanism used by the virus pathogen to promote its transmission and long-term survival.
In summary, SARS-CoV-2 infection has been associated with altered brain function which may lead to new onset or worsening of preexisting neuropsychiatric symptoms. Recent studies have considered both the direct and indirect impact of SARS-CoV-2 infection on the CNS. Among these findings, prolonged COVID-19 (also known as “long COVID”) may lead to serious long-term mental and cognitive changes, including the condition known as “brain fog”. Neuronal cell energy metabolism may become compromised upon integration of the viral genome, resulting in mitochondrial dysfunction and distinct regions of cerebral hypoxia. As discussed, hypoxic conditions in the CNS may facilitate virus reproduction. Cerebral tissues require an immediate and constant supply of oxygen to maintain physiologic function. Thus, when confronted with hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment serves to benefit the viral pathogen, as infected individuals exhibit behaviors that limit protection against infection. The capacity to target cellular mitochondria may also provide an evolutionary advantage for SARS-CoV-2. A high viral load detected in COVID-19 patients with CNS-related symptoms suggests that neurons with high-level energy needs have been compromised. Therefore, it is proposed that the selective targeting of neuronal mitochondria during SARS-CoV-2 infection affects cognitive processes and results in “brain fog” and behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 are clearly of increasing significance with respect to patient diagnosis, prognosis, and the need for long-term care. Furthermore, this cloaked abeyant nature of certain pathogens and/or their metabolites may represent initiating neuropsychiatric and/or neurodegenerative phenomena that currently eludes detection. Taken together, there is an increasing need for mental health support for issues related to acute and chronic pathogen actions, e.g., COVID-19 (Huang et al., 2018; von Arnim et al., 2019).
Acknowledgments
The Department of Psychiatry, First Faculty of Medicine, Charles University in Prague, Czech Republic is noted for hosting this project.
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