Postacute COVID, high lactate levels and mitochondrial dysfunction

The patients with postacute sequelae of SARS-CoV-2 infection (PASC) exhibit markers of a systemic acid-base imbalance. This retrospective study from US researchers examined rates of fatty acid oxidation (FATox) and lactate clearance during graded exercise in patients with PASC using cardiopulmonary exercise test (CPET). According to the authors, the observed rises in blood lactate levels early in the exercise session and decreased rates of FATox during exercise suggest mitochondrial dysfunction and “metabolic reprogramming” in patients with postacute COVID.

The acid-base balance in COVID-19

Under normal physiological conditions, the arterial blood pH is between 7.35 and 7.45. Acidosis is a condition characterized by a decrease in the blood pH below 7.35. A distinction is made between respiratory acidosis, which is caused by difficulty in removing carbon dioxide by the lungs, and metabolic acidosis, which can have various causes such as loss of bicarbonate, elevated acid production, and reduced ability of the kidneys to excrete excess acids. There are two types of metabolic acidosis, lactic acidosis and ketoacidosis. Lactic acidosis is defined as concentration of lactate above 2 mM.

Previous studies demonstrated that acidosis is often associated with a severe form of COVID-19. Inflammation reduces microvascular blood flow through inflammation of endothelial cells, aggregation of platelets and erythrocytes, clotting and formation of neutrophil extracellular traps. When small vessels are damaged, hypoxia shifts metabolism toward glycolysis and anaerobic respiration. This leads to the accumulation of lactate. During the oxidative burst that often accompanies inflammation, neutrophils produce a massive number of protons. Liao et al. proposed that SARS-CoV-2, through interaction with ACE2 receptors, can affect the renin-angiotensin-aldosterone system and disrupt the proton excretion and normal regulation of pH by the kidneys. Nechipurenko YD. The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19. Biology (Basel). 2021 Sep; 10(9): 852.

The productive entry of SARS-CoV-2 and the infection rate are sensitive to changes in pH. It was shown that SARS-CoV-2 cell entry, in particular S protein membrane fusion and genome penetration, requires virion exposure to an acidic milieu of pH < 7 ( 6.2 to 6.8). PNAS 2022; 119 (38) e2209514119.

Similarly, adding the SARS-CoV-2 pseudovirus which contains the S protein to a culture of human ACE2-overexpressing cells caused a higher rate of viral infection at pH of 6.8 than at a normal pH of 7.4. Conversely, a pH of 7.8 reduced infection efficiency compared to pH of 7.4, indicating weak alkaline inhibition of SARS-CoV-2 infection. VIEW. 2022;3:20220004.

Therefore, several authors suggested the existence of a positive feedback loop and a potential vicious cycle, indicating that acidosis induced by SARS-CoV-2 infection enhances SARS-CoV-2 infection. Acidosis promotes chronic inflammation both locally and in a general way due to the production of large amounts of pro-inflammatory cytokines and the recruitment of immune cells. An increase in lactate concentration is associated with increased inflammation and increased risk of thromboembolism. It has been shown that increased likelihood of fatality for patients with COVID-19 is associated with lactate concentrations above 2 mM.

About the study

The US researchers used cardiopulmonary exercise test (CPET) in patients with PASC to calculate rates of FATox and lactate clearance, providing insight into mitochondrial function. The data were obtained through a retrospective review of the electronic medical records of a cohort of 50 subjects with PASC (n=50, 35 female).

The mean time from COVID-19 diagnosis to CPET was 6±4 months. The patients were tested on a cycle ergometer using a continuous ramp protocol to exhaustion. Cardiovascular, ventilatory, metabolic, and gas exchange data were collected. Within 2±3 months of CPET, a resting echocardiogram performed in 39 patients (78%) showed normal left ventricular systolic function (ejection fraction 5070%) in all patients.

Results showed that VO2max, the maximum rate of oxygen consumption attainable during physical exercise, was normal in 34 (68%) patients and reduced in 16 (32%) patients. 

However, the results also showed that 39 patients with PASC with or without comorbidities had higher mean lactate level early in the exercise session. Furthermore, all 50 patients with PASC had significantly lower calculated rates of FATox during exercise when compared to cohorts of moderately active individuals or individuals with metabolic syndrome.

The authors stated that blood lactate levels are expected to rise during high exercise intensity, as the glycolytic flux exceeds the rate of mitochondrial pyruvate oxidation. However, the findings of high arterial lactate levels early in an exercise session at a relatively low exercise intensity (e.g., >9 mM at 150W) in patients with PASC suggest that the transition from FATox to carbohydrate oxidation occurred prematurely. According to the authors, these results suggest mitochondrial dysfunction and “metabolic reprogramming”.

The mechanism by which SARS-CoV-2 may disrupt mitochondrial metabolism is not known. The scientists concluded that abnormally low FATox and a change in lactate production in skeletal muscle are thought to be a cause of- or contribute to- the functional limitations in patients with PASC. But, they emphasized that long-term muscle weakness observed in COVID-19 survivors could be a consequence of a heterogeneous muscle pathology and not solely due to a diminished content of mitochodria.

This article was published in American Journal of Respiratory and Critical Care Medicine.

Journal Reference

de Boer,E et al. Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome. American Journal of Respiratory and Critical Care Medicine 2022; 205 No 1. (Open Access)

The findings of this study indicated that PASC patients had abnormally high blood lactate after even mild exertion, suggesting metabolic dysfunction and muscle acidosis. Based on these data, some authors hypothesized that metabolic dysfunction and a shift to anaerobic respiration can affect every organ system and underpin the symptoms of PASC. Front. Immunol 2023; 14:1150105

In the year 2020, some authors suggested that understanding the pathways underlying interaction of SARS-CoV-2 with host mitochondria could provide critical insights into COVID-19 pathologies. They suggested that drugs that selectively restore mitochondrial functions and promote mitochondrial biogenesis might be used as anti-inflammatory agents to prevent or treat COVID-19. Singh KK. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol 2020; 319: C258 –C267.