Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk

Enrico Zampese, Cristina Fasolato, Maulilio J. Kipanyula, Mario Bortolozzi, Tullio Pozzan*, Paola Pizzo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

231 Scopus citations

Abstract

Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca2+ homeostasis, and their FAD-linked mutants affect cellular Ca2+ handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca2+ content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activity and increasing ER Ca2+ leak. Here we focus on the effect of presenilins on mitochondrial Ca2+ dynamics. By using genetically encoded Ca2+ indicators specifically targeted to mitochondria (aequorin- and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca2+ shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca2+ transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca2+-uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca2+ hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis.

Original languageEnglish (US)
Pages (from-to)2777-2782
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number7
DOIs
StatePublished - Feb 15 2011

Keywords

  • Fluorescence resonance energy transfer
  • Fluorescent Ca probe
  • Intracellular organelle tethering

ASJC Scopus subject areas

  • General

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