The central role of mitochondrial fitness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic

Abstract

Mitochondria are central regulators of cellular metabolism, most known for their role in energy production. They can be "enhanced" by physical activity (including exercise), which increases their integrity, efficiency and dynamic adaptation to stressors, in short "mitochondrial fitness". Mitochondrial fitness is closely associated with cardiorespiratory fitness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory fitness is also an integral determinant of the antiviral host defense and vulnerability to infection. Here, we first briefly review the role of physical activity in viral infections. We then summarize mitochondrial functions that are relevant for the antiviral immune response with a particular focus on the current Coronavirus Disease (COVID-19) pandemic and on innate immune function. Finally, the modulation of mitochondrial and cardiorespiratory fitness by physical activity, aging and the chronic diseases that represent the most common comorbidities of COVID-19 is discussed. We conclude that a high mitochondrial - and related cardiorespiratory - fitness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory fitness of COVID-19 patients and the promotion of physical activity - with all its associated health benefits - as preventive measures against viral infection.

Keywords: COVID; Cardiorespiratory fitness; Exercise; Immune system; Mitochondria; Physical activity; Virus.

Fig. 1

Factors of mitochondrial fitness. Nutrients such as glucose or fatty acids enable tricarboxylic acid (TCA) cycle activity and oxidative phosphorylation (OXPHOS). During OXPHOS reactive oxygen species (ROS) are produced and ROS-levels are massively increased, when the OXPHOS system is dysfunctional. Mitochondria are directly involved in the innate immune response and inflammation by RIG-1 like receptor (RLR) activated mitochondrial antiviral signaling (MAVS) system and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome interaction. Mitochondria can change their morphology by fusion or fission with functional implications, for example on mitochondrial localization, mitochondrial quality control or bioenergetics efficiency. They increase their numbers or density by mitochondrial biogenesis and control cell death and differentiation. An important alternative pathway to OXPHOS to generate energy in the form of adenosine triphosphate (ATP) is glycolysis.

Fig. 2

Parameters of mitochondrial fitness in different tissues that can be modulated by physical activity (PA). Specific effects on distinct tissues are shown only for chronic moderate intensity PA due to the scarcity of data for other conditions. Effects that are potentially more pronounced than in other modalities and may represent distinguishing features are highlighted in red. While the indicated effects of PA on mitochondrial functions are established for human skeletal muscle, evidence on mitochondrial benefits in remote tissues are more scarce. While enhanced mitochondrial biogenesis, oxidative phosphorylation (OXPHOS) and anti-oxidant capacities have been convincingly shown in response to PA in various tissues in rodents [16], more research is needed to fully understand exercise effects on mitochondria. However, rodent pathology models support the assumption of the potential of PA to rescue mitochondrial fitness also in other tissues [19] and for other mitochondrial functions, such as mitochondrial dynamics [232]. This aspect has recently been discussed for human brain [233] and the mode of communication of PA effects to other tissues has been outlined recently as well [234]. ROS - reactive oxygen species. . (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)