A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Genetics. 2015 Dec;201(4):1453-66. doi: 10.1534/genetics.115.182808. Epub 2015 Oct 23.


Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) ∼20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, γ-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.

Keywords: Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / physiology*
  • Calcium / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Homeostasis
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mitochondria / physiology*
  • Mitochondria / ultrastructure
  • Mutation
  • Presenilins / genetics
  • Presenilins / physiology*


  • Caenorhabditis elegans Proteins
  • Membrane Proteins
  • Presenilins
  • SEL-12 protein, C elegans
  • Amyloid Precursor Protein Secretases
  • Calcium