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


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


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


METHODS
We studied adult prolonged critically ill patients vs. controls.


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


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


RESULTS
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.


CONCLUSIONS
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.
Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. ilse.vanhorebeek@med.kuleuven.be
Ilse
I
Vanhorebeek
Jan
J
Gunst
Sarah
S
Derde
Inge
I
Derese
Magaly
M
Boussemaere
André
A
D'Hoore
Pieter J
PJ
Wouters
Greet
G
Van den Berghe
D000328:Adult; D001344:Autopsy; D001706:Biopsy; D016022:Case-Control Studies; D016638:Critical Illness; D048749:Cytokinesis / Q000502:physiology*; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008561:Membrane Fusion / Q000502:physiology; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000473:pathology / Q000502:physiology; D008954:Models, Biological; D052097:Quadriceps Muscle / Q000473:pathology / Q000648:ultrastructure