Survival in critical illness is associated with early activation of mitochondrial biogenesis.
BACKGROUND
We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality.


OBJECTIVE
To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients.


METHODS
Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery.


RESULTS
Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor γ coactivator 1-α (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio.


CONCLUSIONS
Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).
Bloomsbury Institute for Intensive Care Medicine, Department of Medicine and Wolfson Institute of Biomedical Research, University College London, London, United Kingdom.
Jane E
JE
Carré
Jean-Christophe
JC
Orban
Lorenza
L
Re
Karen
K
Felsmann
Wiebke
W
Iffert
Michael
M
Bauer
Hagir B
HB
Suliman
Claude A
CA
Piantadosi
Terry M
TM
Mayhew
Patrick
P
Breen
Martin
M
Stotz
Mervyn
M
Singer
D000368:Aged; D016022:Case-Control Studies; D016638:Critical Illness / Q000401:mortality*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009102:Multiple Organ Failure / Q000378:metabolism / Q000401:mortality*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D024101:Mitochondrial Proteins; D014157:Transcription Factors