Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness

Abstract

Background Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. Methods To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. Results We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. Conclusion Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies.

Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population

“…For instance, a previous study observed a rapid increase in extracellular free thiols following transient hypothermia-induced vasoconstriction in patients with primary Raynaud's phenomenon and systemic sclerosis [ 42 ]. Another example constitutes a study in which extracellular free thiols were observed to change dramatically over the course of several days in patients having critical illness [ 43 ]. These observations underscore the reversibility and dynamic nature of processes that are related to oxidative modification of extracellular free thiols, thereby lowering their total availability in the systemic circulation.…”

Skeletal muscle alterations in patients with acute Covid‐19 and post‐acute sequelae of Covid‐19

“…Mitochondrial dysfunction and metabolic alterations are typically observed in patients with critical illness myopathy 66 . Suppression of fatty acid oxidation and NADH‐linked (mitochondrial complex I‐supported) respiration occur within days of admission to the ICU 67 . Sepsis triggers profound long‐lasting ultrastructural defects in skeletal muscle mitochondria 68,69 .…”

“…Recovery from critical illness is strongly associated with restoration of oxidative phosphorylation 67 and the activation of mitochondrial biogenesis, 70 with eventual survivors showing higher intramuscular ATP content than non‐survivors 69 . Low muscle mitochondrial content in ICU survivors contributes to long‐term weakness 73 .…”

Exercise Training Induces a Shift in Extracellular Redox Status with Alterations in the Pulmonary and Systemic Redox Landscape in Asthma

“…These seemingly counterintuitive changes may be explained by the need for redox balance at the whole-body level. There is supportive evidence for this explanation in the literature, with demonstration of opposing changes in glutathione redox status within plasma and erythrocytes in critically ill patients [ 50 ] and in healthy individuals subjected to acute aerobic exercise [ 51 ]. Alternatively, the lower GSSG levels after exercise may be reflective of an increased capacity for reduction in skeletal muscle.…”