Abstract
Background & Aim: Autophagy is a cytoprotective recycling
mechanism, capable of digesting dysfunctional cellular components, and
this process is associated with pro-survival outcomes. Autophagy may
decline in the aging myocardium, thereby contributing to cardiac
dysfunction. However, it remains to be established how autophagy
responds to ischemia-reperfusion stress with age.
Methods: Samples from the right atrium were collected from
young (≤50 years; n=5) and aged (≥70 years; n=11) patients prior to and
immediately following cardioplegic arrest during coronary artery bypass
grafting (CABG) surgery, a model of human ischemia-reperfusion injury.
Results: Mitochondrial content did not differ between the age
groups, however a 32% reduction in UQCRC2 (0.74 vs 0.53, effect of age,
p=0.03) was seen with age, indicating possible compositional
disruptions. In response to IR, VDAC (0.75 vs 1.05, p=0.03) and COX-I
protein (0.63 vs 1.10, p=0.03) was over expressed in young, but not in
aged patients. Reductions in Parkin (0.95 vs 0.49, interaction effect,
p=0.04) and NIX (0.60 vs 0.21, p=0.004) protein expression with age
suggest an impairment in mitochondrial recycling, which may lead to an
accumulation of dysfunctional mitochondria. Following IR, our data
suggest that in the young cohort, autophagy is reduced as a Beclin-1
decreased by 63% (0.95 vs 0.36, p=0.001) and no changes were observed
in either p62 or LC3-II:I ratio.
Conclusion: Our data demonstrate a blunted cardiac
mitochondrial response to ischemia with age, accompanied by a possible
impairment in mitophagy. These findings support an age-associated
inability of the atrial myocardium to mount appropriate adaptive
responses to stress.