PINK1 protein levels are reduced in end-stage human heart failure, and PINK1 knockout mice develop left ventricular dysfunction, hypertrophy, and impaired mitochondrial function by 2 months of age.
Does loss of PINK1 cause mitochondrial and cardiac dysfunction?
PINK1 is essential for maintaining mitochondrial function, redox homeostasis, and normal cardiac function, with its loss leading to early-onset heart failure phenotypes in mice.
Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) production and the ability of an organism to eliminate these toxic intermediates. Mutations in PTEN-inducible kinase 1 (PINK1) link mitochondrial dysfunction, increased sensitivity to ROS, and apoptosis in Parkinson's disease. Whereas PINK1 has been linked to the regulation of oxidative stress, the exact mechanism by which this occurs has remained elusive. Oxidative stress with associated mitochondrial dysfunction leads to cardiac dysfunction and heart failure (HF). We hypothesized that loss of PINK1 in the heart would have deleterious consequences on mitochondrial function. Here, we observed that PINK1 protein levels are markedly reduced in end-stage human HF. We also report that PINK1 localizes exclusively to the mitochondria. PINK1(-/-) mice develop left ventricular dysfunction and evidence of pathological cardiac hypertrophy as early as 2 mo of age. Of note, PINK1(-/-) mice have greater levels of oxidative stress and impaired mitochondrial function. There were also higher degrees of fibrosis, cardiomyocyte apoptosis, and a reciprocal reduction in capillary density associated with this baseline cardiac phenotype. Collectively, our in vivo data demonstrate that PINK1 activity is crucial for postnatal myocardial development, through its role in maintaining mitochondrial function, and redox homeostasis in cardiomyocytes. In conclusion, PINK1 possesses a distinct, nonredundant function in the surveillance and maintenance of cardiac tissue homeostasis.
Billia et al. (Mon,) conducted a other in Heart failure. PINK1 knockout was evaluated on Cardiac function and mitochondrial function. PINK1 protein levels are reduced in end-stage human heart failure, and PINK1 knockout mice develop left ventricular dysfunction, hypertrophy, and impaired mitochondrial function by 2 months of age.