Presenilin mutations deregulate mitochondrial Ca²⁺ homeostasis and metabolic activity causing neurodegeneration in <i>Caenorhabditis elegans</i>.

Abstract

Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (<i>PSEN1</i> and <i>PSEN2</i>) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the <i>C. elegans</i> gene encoding a PSEN homolog, <i>sel-12</i> result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In <i>sel-12</i> mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca²⁺ signaling leads to an increase in mitochondrial Ca²⁺ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca²⁺ release, mitochondrial Ca²⁺ uptake or mitochondrial superoxides in <i>sel-12</i> 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 Ca²⁺ signaling and provide insight for alternative targets for treating neurodegenerative diseases.