Cytosolic full-length PTEN-induced putative kinase 1 enhances mitophagic potential and mtDNA integrity in angiotensin II-induced hypertensive mice

Abstract

PTEN-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. The primary purpose of this study was to determine the expression and subcellular localization of PINK1 under physiological fluidic conditions in endothelial cells (ECs) and elucidate the implication these phenomena in the endothelial homeostasis and disease prevention. Unidirectional laminar shear stress (LSS) significantly elevated both mRNA and protein expression levels of the full-length PINK1 (FL-PINK1) in ECs. Extensive mitochondrial fractionation assays and confocal microscopic analyses demonstrated significantly reduced FL-PINK1 accumulation in the mitochondrial compartment yet increased in the cytosolic pool of FL-PINK1 after exposed to prolonged high LSS (15 dyne/cm2 for 48h). We also observed that mitophagy flux was significantly decreased without changes in mitochondrial membrane structures and membrane potential under the LSS condition. Moreover, increased cytosolic PINK1 increased mitophagic sensitivity to the cumulative fragmented mitochondria in the ECs. When treated with angiotensin II (AngII), LSS-preconditioning significantly decreased mtDNA lesions and displayed rapid Parkin recruitment followed by mitophagy induction in response to a mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl hydrazone, -mediated oxidative stress condition. In addition, voluntary running exercise-preconditioning showed elevated PINK1 expression and enhanced mitophagy induction and reduced mtDNA lesions in the AngII-induced hypertensive mice. Taken together, LSS specifically increases a cytosolic pool of FL-PINK1, which elevates mitophagic sensitivity to dysfunctional mitochondria in endothelial cells. Our data suggest that enhanced unidirectional laminar shear stress promotes mitochondrial quality control and cell protection mechanisms via a PINK1-dependent pathway. This work was supported by funding from the National Institute of Heart, Lung, and Blood Institute at the National Institutes of Health (R01 HL126952 to J.Y.P.); and The American Heart Association/Beatrice F. Nicoletti research grant (19POST34450157 to J.C.S). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.