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Novel Finding of Mitochondrial Biogenesis During Cardiac Surgery: Marker or Mediator of Ischemia/Reperfusion (I/R) Injury, or an Element of the Homeostatic Intracellular Repair Response (HIR 2 )
Author(s) -
Andres Allen,
Sengstock David,
Jahania Salik,
Dabir Reza,
Tucker Kyle,
Gottlieb Roberta,
Mentzer Robert
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.725.5
Subject(s) - mitophagy , mitochondrial biogenesis , mitochondrion , autophagy , cardioprotection , biology , microbiology and biotechnology , pink1 , reperfusion injury , cytosol , parkin , ischemia , medicine , biochemistry , apoptosis , disease , parkinson's disease , enzyme
BACKGROUND We recently demonstrated that the homeostatic intracellular repair response (HIR 2 ) is activated during cardiac surgery. Part of HIR 2 involves brisk mitochondrial turnover in the heart; a process that comprises both mitophagy and mitochondrial biogenesis. We have previously demonstrated that mitophagy is an important element of ischemic preconditioning. However, it is unknown whether mitochondrial biogenesis occurs in the setting of I/R and how it might contribute to cardioprotection or injury. STUDY DESIGN Autophagy and mitochondrial turnover were assessed in 20 patients undergoing coronary artery bypass or valve surgery requiring cardiopulmonary bypass (CPB). Biopsies of right atrial appendage obtained before initiation and after weaning from CPB were processed for whole tissue lysate, mitochondria‐enriched heavy membrane, and cytosolic fractions. Samples were analyzed for autophagy by immunoblotting for LC3, Beclin‐1, ATG5‐12, and p62. Mitochondrial turnover was assessed by monitoring Tom70, Cox4, and Parkin. Cytosolic cytochrome c was examined as a marker of injury. RESULTS Heart surgery resulted in increased autophagy indicated by depletion of autophagy proteins after bypass. Parkin increased in the mitochondrial fraction and decreased in the cytosol. We observed a marked increase in mitochondrial proteins Tom70 and Cox4, both of which positively correlated with cross‐clamp and bypass time. Cytosolic cytochrome c consistently increased after CPB and correlated with increased mitochondrial mass. CONCLUSIONS These findings provide evidence for the first time in humans that coordinated mitophagy and biogenesis occur in response to I/R. Intriguingly, increased cytosolic cytochrome c after bypass paralleled the increase in mitochondrial mass, raising the concern that mitochondrial biogenesis may contribute to I/R injury. Whether mitochondrial biogenesis is beneficial or a liability in the setting of I/R remains to be clarified. Thus, strategies designed to amplify HIR 2 and/or modulate mitochondrial biogenesis during cardiac stress may represent a novel approach to myocardial protection in patients undergoing heart surgery. Support or Funding Information NIH: P01 HL112730