Mitochondrial Calcium Dysregulation: A Central Nexus in Alzheimer’s Disease Pathogenesis and Therapeutic Intervention

Abstract

Research in Alzheimer’s disease (AD) has been primarily focused on the genetic causes and therapies to target the amyloid‑β (Aβ) plaques and neurofibrillary tau tangles (NFTs). However, a growing body of research suggests that imbalances and subsequent breakdown in mitochondrial calcium (Ca²⁺) regulation plays a central role in the development of AD. Aβ plaques and presenilin (PS) mutations affect endoplasmic reticulum (ER) – mitochondria Ca²⁺ transfer, alter Ca²⁺ channel function, and disrupt intracellular Ca²⁺ buffering. These promote both Aβ plaque accumulation and tau hyperphosphorylation which further disrupt the ER – mitochondria Ca²⁺ transfer driving excessive mitochondrial Ca²⁺ uptake that promotes chronic overload, synaptic degeneration, and eventual neural loss. This creates a self‑amplifying cycle of neurodegeneration. This paper highlights the roles of mitochondrial calcium uniporter (MCU) complex and mitochondrial sodium – calcium – lithium exchanger (NCLX) in regulating mitochondrial Ca²⁺ along with the therapeutic effects of regulating mitochondrial Ca²⁺ in the brain. Benefits and constraints of the current MCU inhibitors are described along with the challenges of using them for treating neurodegenerative diseases. While highlighting progress in understanding the mitochondrial Ca²⁺ pathway, this paper emphasizes the need for a better understanding of the intersection of mitochondrial biology, Ca²⁺ signaling, and neurodegeneration to bring innovative solutions in the treatment of AD that focus on mechanistically precise early interventions that target the root drivers of cognitive decline.