Understanding Long COVID; Mitochondrial Health and Adaptation-Old Pathways, New Problems

Abstract

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can "tip" the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer's metabolism needs to be "tipped" back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.

Keywords: Kreb’s cycle; SARS-CoV-2; hormesis; inflammation; lifestyle; long COVID; metabolic flexibility; mitochondria; platelets.

Figure 1

Some of the many roles of the mitochondrion and the centrality of glycolysis and the tricarboxylic acid cycle (TCA, also known as the Kreb’s cycle).

Figure 2

Potential viral manipulation of mitochondrial function in multiple cell types could be allied with symptoms of long COVID; the virus manipulates the system towards growth pathways that are similar to inflammatory pathways, which are also how the host tries to get rid of the virus.

Figure 3

Why a poor lifestyle might lead to a greater likelihood of long COVID. Poor metabolic flexibility, as a result of a lifestyle that does not stimulate optimal mitochondrial function, can result in low grade inflammation that may well further stress mitochondrial function. On exposure to the virus, the system is further tipped towards an inflammatory phenotype, which coupled with sub-optimal mitochondrial function in the immune system, may take longer to either clear the virus and/or resolve the proinflammatory state.

Figure 4

Why a good lifestyle may help against the long COVID. With mitochondria in optimal health, they have plenty of reserve capacity to ensure the metabolic flexibility to both ensure a good immune response, and also, for instance, via effective antioxidant capability, ensure inflammation is resolved.

Figure 5

Tipping the system back to health. As long COVID might be represented by the upper see saw whereby the metabolic flexibility fulcrum is too far to the right to enable the restoration of homeostasis, the system has effectively passed a tipping point and got stuck. Resolution may revolve around enhancing metabolic flexibility and/or suppressing inflammatory pathways to shift the fulcrum to the left, as in the lower see saw. At the simplest level, someone starting with a reduced population of slightly stressed mitochondria could well be more likely to develop long COVID—which implies, for resolution, that the system needs to be induced to adapt towards normal by hormetic approaches known to stimulate renewal of a healthy population of mitochondria. The most obvious of these is a carefully balanced prescription of physical activity.