β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models

Abstract

BackgroundMitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer’s disease–affected brains by yet unexplained mechanisms. MethodsWe combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog–induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus–infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry. ResultsWe show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to γ-secretase activity and β-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a–dependent manner. Interestingly, the modulation of γ-secretase activity or AICD expression affects Pink-1–related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. ConclusionsOverall, we delineate a molecular cascade presenilins–AICD–Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1–dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin–Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.