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Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass
Allen M. Andres, … , Robert M. Mentzer Jr., Roberta A. Gottlieb
Allen M. Andres, … , Robert M. Mentzer Jr., Roberta A. Gottlieb
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e89303. https://doi.org/10.1172/jci.insight.89303.
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Research Article Cardiology Cell biology

Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass

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Abstract

Mitophagy occurs during ischemia/reperfusion (I/R) and limits oxidative stress and injury. Mitochondrial turnover was assessed in patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB). Paired biopsies of right atrial appendage before initiation and after weaning from CPB were processed for protein analysis, mitochondrial DNA/nuclear DNA ratio (mtDNA:nucDNA ratio), mtDNA damage, mRNA, and polysome profiling. Mitophagy in the post-CPB samples was evidenced by decreased levels of mitophagy adapters NDP52 and optineurin in whole tissue lysate, decreased Opa1 long form, and translocation of Parkin to the mitochondrial fraction. PCR analysis of mtDNA comparing amplification of short vs. long segments of mtDNA revealed increased damage following cardiac surgery. Surprisingly, a marked increase in several mitochondria-specific protein markers and mtDNA:nucDNA ratio was observed, consistent with increased mitochondrial biogenesis. mRNA analysis suggested that mitochondrial biogenesis was traniscription independent and likely driven by increased translation of existing mRNAs. These findings demonstrate in humans that both mitophagy and mitochondrial biogenesis occur during cardiac surgery involving CPB. We suggest that mitophagy is balanced by mitochondrial biogenesis during I/R stress experienced during surgery. Mitigating mtDNA damage and elucidating mechanisms regulating mitochondrial turnover will lead to interventions to improve outcome after I/R in the setting of heart disease.

Authors

Allen M. Andres, Kyle C. Tucker, Amandine Thomas, David J.R. Taylor, David Sengstock, Salik M. Jahania, Reza Dabir, Somayeh Pourpirali, Jamelle A. Brown, David G. Westbrook, Scott W. Ballinger, Robert M. Mentzer Jr., Roberta A. Gottlieb

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Figure 2

Changes in mitochondrial proteins and mtDNA content during cardiac surgery.

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Changes in mitochondrial proteins and mtDNA content during cardiac surge...
(A) Western blot analysis of representative mitochondrial markers in whole tissue lysates from atrial samples before (A, circles) and after (B, squares) cardiac surgery (n = 20 patient sets). (B) Quantitation of Western blots, including the representative one shown above. Solid symbols correspond to the densitometric quantitation of lanes from exposure 1 (short exposure), and open symbols correspond to exposure 2 (long exposure). Representative Ponceau-stained membrane used for normalization is shown to right. (C) Representative Western blot of mitochondrial inner (CoxIV) and outer (Tom70) membrane shown with results plotted to examine correlation in response to CPB (10 patient sets plotted). (D) mtDNA:nucDNA ratio was determined by qPCR of mitochondrial and nuclear encoded DNA markers (n = 16 patient sets) before (A, solid circles) and after CPB (B, solid squares). Data represent mean ± SEM. *P < 0.05; #P < 0.01. Student t test (A and D), linear regression (C).

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