Presenilin mutations deregulate mitochondrial Ca < sup > 2+ < /sup > homeostasis and metabolic activity causing neurodegeneration in < i > Caenorhabditis elegans < /i >

Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 andPSEN2) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in theC. elegans gene encoding a PSEN homolog,sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. Insel-12 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 insel-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 Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases.
Source: eLife - Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research