Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans

Abstract

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 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 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 Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases.

Role of Presenilin in Mitochondrial Oxidative Stress and Neurodegeneration in <em>Caenorhabditis elegans</em>

“…Therefore, given the elevation in ER-calcium release observed in sel-12 mutants, the mitochondrial calcium level was examined. Strikingly, mitochondrial calcium levels are elevated in both the neurons and body wall muscles of sel-12 mutants and this phenotype could be suppressed by reducing ER calcium release or mitochondrial calcium uptake (Sarasija et al, 2018). These data are consistent with elevated ER calcium release and, importantly, mitochondrial calcium uptake in sel-12 mutants.…”

“…Acceleration of oxidative phosphorylation could result in downstream deleterious effects due to an overproduction of ROS, a product of cellular respiration. Consistent with increased ER-mitochondrial calcium signaling and oxidative phosphorylation, young adult sel-12 mutants display elevated oxygen consumption rates and increased levels of ROS (Sarasija et al, 2018). Strikingly, similar elevation in oxygen consumption rates and ROS levels were observed in functional astrocytes from induced pluripotent stem cells (iPSCs) derived from AD patients with PSEN1 mutations suggesting a conserved role for presenilin in mitochondrial respiration and ROS homeostasis (Oksanen et al, 2017).…”

“…Taken together, these data indicate that presenilin mutations cause increased ER-calcium release, subsequent mitochondrial calcium uptake and concomitant increase in mitochondrial respiration, which results in overproduction of ROS. In contrast to young adult sel-12 mutants, analysis of oxygen consumption rate in older adult sel-12 mutants was drastically reduced compared to similarly aged wild type animals, indicating that the high level of mitochondrial respiration in young adult sel-12 mutants cannot be maintained and deteriorates as the mutants age (Sarasija et al, 2018).…”

“…Markedly, ROS levels were significantly higher in sel-12 mutants compared to wild type control animals (Sarasija and Norman, 2015). Moreover, reduction of ER-mitochondrial calcium signaling reduces the levels of ROS observed in sel-12 mutants (Sarasija et al, 2018), indicating that the high ROS production in sel-12 mutants is caused by increased ER to mitochondria calcium transfer. Similar to the astrocytes from iPSCs derived from EOFAD patients harboring PSEN1 lesions (Oksanen et al, 2017), fibroblasts isolated from EOFAD patients harboring different PSEN1 mutations also showed elevated levels of ROS (Sarasija et al, 2018).…”

“…Moreover, reduction of ER-mitochondrial calcium signaling reduces the levels of ROS observed in sel-12 mutants (Sarasija et al, 2018), indicating that the high ROS production in sel-12 mutants is caused by increased ER to mitochondria calcium transfer. Similar to the astrocytes from iPSCs derived from EOFAD patients harboring PSEN1 lesions (Oksanen et al, 2017), fibroblasts isolated from EOFAD patients harboring different PSEN1 mutations also showed elevated levels of ROS (Sarasija et al, 2018). Moreover, it was found that blocking mitochondrial calcium uptake in these cells using the mitochondrial calcium uniporter inhibitor, Ru360, could suppress the elevated ROS levels observed in the EOFAD patient fibroblast.…”