PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function

Abstract

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.mitochondrial swelling | mitochonopathy | mitochondrial energetics H eart failure (HF) is the inability of the heart to adequately pump blood to meet the demands of the body. It is the leading cause of morbidity and mortality in North America (1). The quality of life and the prognosis for this group of patients remains poor with 1-y survival rates less than 40% (1). Conventional pharmacological therapy, which only slows the progression of the disease by alleviating the workload of the heart, does not directly target the disease process itself. Alternatives to medical therapy are limited to transplantation or mechanical assist devices; approaches that are themselves associated with significant morbidity and mortality. As such, it is exceedingly important to discover alternate strategies that will effectively treat this disease entity.Oxidative stress is created by the imbalance between production of reactive oxygen species (ROS) and the elimination of toxic intermediates by antioxidant systems. The heart with its high metabolic state and limited capacity for regeneration is particularly sensitive to oxidative stress. Upon exposure to ROS, the heart undergoes hypertrophic growth, a process that involves cell enlargement, myofibrillar disarray, and reexpression of fetal genes (2). Although cardiac hypertrophy is considered an initial adaptive response, prolonged hypertrophy is ultimately detrimental and leads to progressive HF.The discovery of recessively inherited mutations in PTENinducible ...

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Drosophila as a Model to Study Mitochondrial Dysfunction in Parkinson's Disease

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