RESUMO
PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK152, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy.
Assuntos
Mitocôndrias/metabolismo , Mitofagia , Proteínas Quinases/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Citosol/enzimologia , Células HEK293 , Células HeLa , Humanos , Leupeptinas/farmacologia , Membranas Mitocondriais/enzimologia , Doença de Parkinson/enzimologia , Inibidores de Proteassoma/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Proteólise , Valinomicina/farmacologiaRESUMO
BACKGROUND: Obesity is characterized by insulin resistance and hyperinsulinemia that may elevate arterial pressure due to sympathetic overactivity and volume overload. The aim of the study is to measure hemodynamic parameters and metabolic variables in obese normotensive subjects. METHODS: Twenty-four normotensive, overweight subjects from our medical staff were enrolled. They had personal and group meetings with a physician, dietician, and psychologist to improve their compliance with regard to physical activity and personal low-calorie diet. In addition, each subject was given orlistat 120 mg three times daily for 12 weeks. Noninvasive hemodynamic parameters including arterial compliance were measured using radial artery pulse wave analysis, at the beginning and 1 month after taking the last dose of Orlistat, and insulin resistance was calculated using HOMA score. RESULTS: At the end of the 3-month period, the average weight was reduced from 89.5 +/- 12 kg to 81.5 +/- 9 kg. The systolic arterial pressure was reduced from 128 +/- 12 mm Hg to 121 +/- 10 mm Hg and diastolic arterial pressure was reduced from 75.4 +/- 9 mm Hg to 69.6 +/- 7 mm Hg. Arterial compliance measurements showed significant improvement in large artery compliance from 13 +/- 4 to 15.8 +/- 3.6 while no change occurred in small arteries. The insulin sensitivity assessed by HOMA score improved significantly from 6.5 +/- 4.5 to 4.8 +/- 3.1 with weight reduction. CONCLUSIONS: Our data show that weight loss is accompanied by lowering of blood pressure, even in normotensive obese patients. This weight loss brings about an improvement in insulin resistance and a rise in large artery compliance, whereas no change occurs in small artery compliance.
