Mitochondrial Calcium Signaling as a Therapeutic Target for Alzheimer’s Disease

Aston J. Wu, Benjamin C. K. Tong, Alexis S. Huang, Min Li, King Ho Cheung*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

15 Citations (Scopus)


Mitochondria absorb calcium (Ca2+) at the expense of the electrochemical gradient generated during respiration. The influx of Ca2+ into the mitochondrial matrix helps maintain metabolic function and results in increased cytosolic Ca2+ during intracellular Ca2+ signaling. Mitochondrial Ca2+ homeosta-sis is tightly regulated by proteins located in the inner and outer mitochondrial membranes and by the cross-talk with endoplasmic reticulum Ca2+ signals. Increasing evidence indicates that mitochondrial Ca2+ overload is a pathological phenotype associated with Alzheimer’s Disease (AD). As intracellular Ca2+ dysregulation can be observed before the appearance of typical pathological hallmarks of AD, it is believed that mitochondrial Ca2+ overload may also play an important role in AD etiology. The high mi-tochondrial Ca2+ uptake can easily compromise neuronal functions and exacerbate AD progression by impairing mitochondrial respiration, increasing reactive oxygen species formation and inducing apopto-sis. Additionally, mitochondrial Ca2+ overload can damage mitochondrial recycling via mitophagy. This review will discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharma-cotherapies that target this dysregulation. As most of the current AD therapeutics are based on amyloi-dopathy, tauopathy, and the cholinergic hypothesis, they achieve only symptomatic relief. Thus, deter-mining how to reestablish mitochondrial Ca2+ homeostasis may aid in the development of novel AD therapeutic interventions.

Original languageEnglish
Pages (from-to)329-343
Number of pages15
JournalCurrent Alzheimer Research
Issue number4
Publication statusPublished - Apr 2020

Scopus Subject Areas

  • Neurology
  • Clinical Neurology

User-Defined Keywords

  • Alzheimer’s disease
  • Calcium
  • Hyperphosphorylation
  • Intracellular neurofibrillary tangles
  • Mitochondria
  • Neurodegenerative disorder


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