Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy
Background—Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular (LV) failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated.
Methods and Results—To characterize mt morphology, biogenesis and genomic integrity in human HF, we investigated LV tissue from non-failing (NF) hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared to ICM or NF hearts. Mt volume density and mtDNA copy number was increased by ~2-fold (P<0.001) in DCM hearts in comparison to ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 vs NF hearts, P<0.05 vs ICM).
Conclusions—In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a PGC-1α- dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.
- Received January 10, 2013.
- Revision received March 15, 2013.
- Accepted March 21, 2013.