Journal Article

Survival in Critical Illness Is Associated with Early Activation of Mitochondrial Biogenesis

Mayhew, Terry M., Re, Lorenza, Suliman, Hagir B., Singer, Mervyn, Stotz, Martin, Carré, Jane E., Iffert, Wiebke, Orban, Jean-Christophe, Felsmann, Karen, Bauer, Michael, Piantadosi, Claude A., Breen, Patrick

2010

Overview

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

• Publisher: American Thoracic Society,Oxford University Press
• Subject: Aged / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / B. Critical Care / Biological and medical sciences / Case-Control Studies / Critical Illness - mortality / Emergency and intensive cardiocirculatory care. Cardiogenic shock. Coronary intensive care / Energy Metabolism / Female / Humans / Intensive care medicine / Male / Medical sciences / Middle Aged / Mitochondria, Muscle - metabolism / Mitochondria, Muscle - pathology / Mitochondrial Diseases - physiopathology / Mitochondrial Proteins - metabolism / Multiple Organ Failure - metabolism / Multiple Organ Failure - mortality / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Survival Rate / Time Factors / Transcription Factors - metabolism