Mitochondrial fusion, fission, and biogenesis in prolonged critically ill patients

Critical illness induces swelling, enlargement, and dysfunction of mitochondria, which in liver, but not in muscle, is aggravated by excessive hyperglycemia. We previously demonstrated impaired autophagic clearance of damaged mitochondria in fed prolonged critically ill patients. Impaired fusion/fission-mediated repair and/or renewal through biogenesis may further accentuate mitochondrial abnormalities.

We studied mitochondrial fusion/fission and biogenesis and how these are affected by preventing hyperglycemia with insulin during critical illness.

Patients admitted to a university hospital surgical/medical intensive-care unit participated in a randomized study.

We studied adult prolonged critically ill patients vs. controls.

Tolerating hyperglycemia up to 215 mg/dl was compared with intensive insulin therapy targeting normoglycemia (80-110 mg/dl).

In liver and skeletal muscle, we quantified levels of several proteins involved in mitochondrial fusion/fission and biogenesis.

Key players in mitochondrial fusion/fission and biogenesis were up-regulated in postmortem liver (1.4- to 3.7-fold) and rectus abdominis (1.2- to 4.2-fold) but not in in vivo or postmortem vastus lateralis biopsies of critically ill patients. Maintaining normoglycemia with insulin attenuated the hepatic response in the mitochondrial fusion/fission process but did not affect the markers of mitochondrial biogenesis in liver or muscle.

Our observations suggest tissue-dependent attempts of compensatory activation of mitochondrial repair mechanisms during critical illness. Considering the previously observed persistent mitochondrial damage, this activation may be insufficient and contribute to mitochondrial dysfunction. Suppressed activation of fusion/fission when excessive hyperglycemia is prevented with insulin may reflect reduced need for diluting (less) damage during normoglycemia or, alternatively, a suppressive effect of insulin on repair.