Kraft, Kelsey

Introduction: Although alterations in mitochondrial function have been observed in senescent hearts, the molecular basis for aging-associated decline in energy metabolism in the human heart is not fully understood. Objective: To determine aging-related changes in functional activity and protein expression level of mitochondrial oxidative phosphorylation (OXPHOS) complexes and expression of genes regulating mitochondrial energetics in the human heart. Methods: Right atrial appendages from well-matched adult (29-57 y.o., n=19) and aged (65-85 y.o., n=22) patients undergoing elective CABG surgery were used. Functional activity of OXPHOS complexes was measured spectrophotometrically. Protein expression level of corresponding OXPHOS protein subunits was determined by Western blot. Gene expression profiling was performed using Affymetrix Human Genome U133 Plus 2.0 microarrays. Results: Mitochondria from senescent hearts demonstrated a significant decrease in complex I and V functional activity without significant changes in the rest of the complexes (Fig. A). At the protein expression level, there was reduction in complex I, III, and IV (Fig. B). This was associated with downregulation of the majority (86%, 90 of 105) of genes coding mitochondrial proteins (Fig. C). Forty-six percent (41 of 90) of the downregulated genes were confined to pathways regulating mitochondrial energetics. Conclusion: With aging, the functional activity of OXPHOS is reduced due to supression of protein expression and downregulation of genes regulating mitochondrial energetics. This provides a substrate for reduced energetic efficiency associated with senescence in the human atria.