25 January 2021: Editorial
Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce ‘Brain Fog’ and Results in Behavioral Changes that Favor Viral SurvivalGeorge B. Stefano ABCDEF* , Radek Ptacek ABCDEF , Hana Ptackova ABCDEF , Anders Martin ABCDEF , Richard M. Kream ABCDEF
Med Sci Monit 2021; 27:e930886
ABSTRACT: Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or ‘long COVID’, also include serious long-term mental and cognitive changes, including the condition recently termed ‘brain fog’. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce ‘brain fog’ and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.
Keywords: Hypoxia, Brain, Mitochondria
Recent studies and clinical observations of SARS-CoV-2 infections have yielded insights into the cellular and physiological processes that enhance the ability of the virus to reproduce and spread, including its need for a highly oxygenated microenvironment . Recently, there has been an increased understanding of the possible role of compromised mitochondria in the pathogenesis of SARS-CoV-2 infection. Mitochondrial energy metabolism responds immediately to a hypoxic microenvironment, and mitochondria can serve as mobile sentinel organelles that can act together as an energy delivery system . Given the high energy and oxygenation requirements in neural tissue, mitochondria can serve as indicators of early acute neuronal dysfunction. The relationship between cognitive function, mental health, virus susceptibility, and viral infectivity may be a function of CNS viral load, which increases with time in the case of ‘long-term COVID’. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit reduced anti-infection behaviors (Figure 1). The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of its interaction with the host. A high viral load in COVID-19 patients that involves the CNS results in the compromise of neurons with high levels of energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce ‘brain fog’ and results in behavioral changes that favor viral survival and propagation. Cognitive changes associated with COVID-19 will have increasing significance in patient diagnosis, prognosis, and long-term care. Therefore, there will be an increasing need for support for mental health issues related to COVID-19. Long-term therapeutic strategies for COVID-19 should combine pharmacological agents targeting a chronic ischemic neural pro-inflammatory environment with behavioral activities to restore cognitive function [29,30].
FiguresFigure 1. ‘Brain fog’ and COVID-19 targeting for long-term rehabilitation. SARS-CoV-2, which causes COVID-19, can infect the lungs, CNS, gastrointestinal system, and cardiovascular system. With time, widespread infection increases the total viral load in the infected individual. SARS-CoV-2 can integrate its genome into mitochondria to reduce energy metabolism. The brain is especially vulnerable to hypoxia because cognitive neural processes adjust poorly to hypoxic conditions. Hypoxia is also pro-inflammatory. Therefore, as the viral load increases, cognitive impairment and confusion increase, a condition known as ‘brain fog’. This ongoing cascade of neuronal dysfunction is an important factor in understanding the long-term pathogenesis of CNS infection with SARS-CoV-2. Importantly, the behaviors resulting from ‘brain fog’ may increase the spread of SARS-CoV-2. COVID-19 – coronavirus disease 2019; SARS-CoV-2 – severe acute respiratory syndrome coronavirus 2; CNS – central nervous system.
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