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

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


Critical illness, Energy metabolism, Mitochondria, Oxidative stress, Redox signaling, Stress physiology
2213-2317
101907
McKenna, Helen T
81be5872-15f4-49a3-a156-33f51d6b234a
O'Brien, Katie A
548aadd1-580b-41e7-bc91-cecd0f8997fe
Fernandez, Bernadette O
9890aabc-1fe6-4530-a51e-31182e537131
Minnion, Magdalena
ab23b32b-9f8e-4876-aaf5-99cb6a725a2f
Tod, Adam
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McNally, Ben D
e64b3652-fa02-471d-8baf-93ab201af973
West, James A
acf1532e-266d-487c-bbe5-87bba31f6c44
Griffin, Julian L
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Grocott, Michael P
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Mythen, Michael G
940f5be7-e5bc-4a90-94aa-09fdc658caad
Feelisch, Martin
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Murray, Andrew J
b4710645-e8f4-4d2e-8a31-cf341f98ed20
Martin, Daniel S
3e441b48-9221-4308-8ae6-49cbde20753f
McKenna, Helen T
81be5872-15f4-49a3-a156-33f51d6b234a
O'Brien, Katie A
548aadd1-580b-41e7-bc91-cecd0f8997fe
Fernandez, Bernadette O
9890aabc-1fe6-4530-a51e-31182e537131
Minnion, Magdalena
ab23b32b-9f8e-4876-aaf5-99cb6a725a2f
Tod, Adam
714c03bc-6b92-4448-b0a1-7d50ea67af0e
McNally, Ben D
e64b3652-fa02-471d-8baf-93ab201af973
West, James A
acf1532e-266d-487c-bbe5-87bba31f6c44
Griffin, Julian L
fdfacaf4-435f-45f9-b84f-375062c94164
Grocott, Michael P
1e87b741-513e-4a22-be13-0f7bb344e8c2
Mythen, Michael G
940f5be7-e5bc-4a90-94aa-09fdc658caad
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Murray, Andrew J
b4710645-e8f4-4d2e-8a31-cf341f98ed20
Martin, Daniel S
3e441b48-9221-4308-8ae6-49cbde20753f

McKenna, Helen T, O'Brien, Katie A, Fernandez, Bernadette O, Minnion, Magdalena, Tod, Adam, McNally, Ben D, West, James A, Griffin, Julian L, Grocott, Michael P, Mythen, Michael G, Feelisch, Martin, Murray, Andrew J and Martin, Daniel S (2021) Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness. Redox Biology, 41, 101907, [101907]. (doi:10.1016/j.redox.2021.101907).

Record type: Article

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.


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Accepted/In Press date: 16 February 2021
e-pub ahead of print date: 20 February 2021
Published date: May 2021
Additional Information: Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021 The Authors
Keywords: Critical illness, Energy metabolism, Mitochondria, Oxidative stress, Redox signaling, Stress physiology

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Local EPrints ID: 447568
URI: http://eprints.soton.ac.uk/id/eprint/447568
ISSN: 2213-2317
PURE UUID: cb5f6f70-7ef6-4177-b91a-fb76aa86c271
ORCID for Bernadette O Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Michael P Grocott: ORCID iD orcid.org/0000-0002-9484-7581
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 16 Mar 2021 17:32
Last modified: 17 Mar 2024 03:31

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Contributors

Author: Helen T McKenna
Author: Katie A O'Brien
Author: Bernadette O Fernandez ORCID iD
Author: Magdalena Minnion
Author: Adam Tod
Author: Ben D McNally
Author: James A West
Author: Julian L Griffin
Author: Michael G Mythen
Author: Martin Feelisch ORCID iD
Author: Andrew J Murray
Author: Daniel S Martin

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