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Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes ( PSEN1  and  PSEN2 ) cause most cases of familial Alzheimer’s disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the  C. elegans  gene encoding a PSEN homolog,  sel-12  result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In  sel-12  mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca 2+  signaling leads to an increase in mitochondrial Ca 2+  content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca 2+  release, mitochondrial Ca 2+  uptake or mitochondrial superoxides in  sel-12  mutants, we demonstrate rescue of the mitochondrial metabolic defects and prevent neurodegeneration. These data suggest that mutations in PSEN alter mitochondrial metabolic function via ER to mitochondrial Ca 2+  signaling and provide insight for alternative targets for treating neurodegenerative diseases.

Presenilin mutations deregulate mitochondrial Ca 2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans