Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, caused by poorly known pathogenic mechanisms and aggravated by delayed therapeutic intervention, that still lacks an effective cure. However, it is clear that some important neurophysiological processes are altered years before the onset of clinical symptoms, offering the possibility of identifying biological targets useful for implementation of new therapies. Of note, evidence has been provided suggesting that mitochondria, pivotal organelles in sustaining neuronal energy demand and modulating synaptic activity, are dysfunctional in AD samples. In particular, alterations in mitochondrial Ca²⁺ signaling have been proposed as causal events for neurodegeneration, although the exact outcomes and molecular mechanisms of these defects, as well as their longitudinal progression, are not always clear. Here, we discuss the importance of a correct mitochondrial Ca²⁺ handling for neuronal physiology and summarize the latest findings on dysfunctional mitochondrial Ca²⁺ pathways in AD, analysing possible consequences contributing to the neurodegeneration that characterizes the disease.

Keywords: Alzheimer's disease; ER-mitochondria contacts; MCU; Mitochondrial calcium signaling; NCLX; Presenilin.