ORCID
- Helen T. McKenna: 0000-0001-9370-6712
- Daniel S. Martin: 0000-0001-6220-8235
Document Type
Article
Abstract
BackgroundNumerous 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.MethodsTo 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.ResultsWe 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.ConclusionCritical 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.
DOI Link
Publication Date
2021-01-01
Publication Title
Redox Biology
Volume
41
ISSN
2213-2317
Acceptance Date
2021-02-16
Deposit Date
2021-04-03
Embargo Period
2021-03-10
Funding
This work was supported by an Intensive Care Society New Investigator Award (2014) and a grant from the Royal Free Charity to DSM. HTM was supported by the London Clinic. AJM received support from The Evelyn Trust. JLG, JAW and BM were supported by the Medical Research Council, UK (MR/P011705/1, MC_UP_A090_1006 and MR/P01836X/1). We are grateful to all of the patients and their families for participating in and supporting this study. We would also like to thank the anonymous reviewers of our work for their insightful comments and suggestions.
Keywords
Critical illness, Stress physiology, Energy metabolism, Mitochondria, Redox signaling, Oxidative stress
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
McKenna, H., O’Brien, K., Fernandez, B., Minnion, M., Tod, A., McNally, B., West, J., Griffin, J., Grocott, M., Mythen, M., Feelisch, M., Murray, A., & Martin, D. (2021) 'Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness', Redox Biology, 41. Available at: 10.1016/j.redox.2021.101907
