Atrial fibrillation is associated with increased susceptibility of mitochondria to permeability transition pore opening


Center for Integrative Research on Cardiovascular Aging

Presentation Notes

Presented at 2013 Aurora Scientific Day, Milwaukee, WI


Background/significance: Although atrial fibrillation (AF) is known to result in progressive electrical, contractile and structural remodeling of the atria with gradual cell loss and replacement fibrosis, the molecular basis for the progressive structural alterations is not fully elucidated. Since mitochondria play an essential role in regulation of cell death through the opening of mitochondrial permeability transition pore (mPTP), we hypothesized that the susceptibility of mitochondria from patients with AF to PTP opening is increased contributing to the substrate that promote progression of AF to long-lasting forms. Purpose: The aim of the study was to characterize the sensitivity of mitochondria to Ca2+-induced mPTP opening in human atria from patients with and without AF.

Methods: Freshly removed left atrial appendage tissue from patients undergoing cardiac bypass surgery with (AF) and without history of AF (nAF) was used for mitochondrial isolation. The sensitivity of mitochondria towards Ca2+-induced mPTP opening was assessed by exposing the isolated mitochondria to sequential additions of 10 μM of Ca2+ and monitoring simultaneously abrupt mitochondrial Ca2+ release (Fluo-5N fluorescence), mitochondrial depolarization (Safranin O fluorescence), and swelling of mitochondrial matrix (decrease in light scattering). Differences in the expression of proteins participating in mPTP formation, including voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), and phosphate carrier protein (PCP) were determined by Western blotting in isolated mitochondria. The protein expression level was expressed in arbitrary units normalized to mitochondrial protein.

Results: The sensitivity of mitochondria to mPTP opening was increased in patients with AF compared to nAF (41±12 vs. 66±8 μM Ca2+). Cyclosporine A, an inhibitor of mPTP, increased tolerance of the mitochondria to Ca2+ loading (74±15 vs. 93±9) and reduced mPTP opening in both group of patients. Increased sensitivity towards mPTP opening in patients with AF was associated with a 2 fold downregulation of the expression of PCP (217±66 vs. 437.6±18) and 2 fold increase in expression of VDAC (428±45 vs. 197±19). A trend towards increased level of expression of ANT was observed in those with AF (900±13 vs. 774±29).

Conclusion: The increased sensitivity of mitochondria from AF patients to mPTP opening can be partly explained by selective downregulation of PCP protein, putative component of mPTP with upregulation of regulatory VDAC and ANT proteins.

Document Type


Link to Full Text