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.
Highlights
In all metazoans, mitochondria are essential organelles and mitochondrial dysfunction is frequently observed in neurodegenerative diseases and aging
Since we previously demonstrated that reducing endoplasmic reticulum (ER) Ca2+ release in sel-12 mutants markedly improved the mitochondrial disorganization that occurs in body wall muscle (Sarasija and Norman, 2015) and given the presence of elevated mitochondrial Ca2+ in sel-12 mutants (Figure 1A, Figure 1—figure supplement 1B), we hypothesized that exacerbated ER Ca2+ signaling in the nervous system is promoting the mechanosensory neuronal defects observed in these animals by causing heightened oxidative phosphorylation (OXPHOS) mediated reactive oxygen species (ROS) production
We provide evidence that mutations in the gene encoding a C. elegans PSEN homolog, sel-12 result in ER to mitochondria Ca2+ signaling defects, elevated mitochondrial Ca2+ levels, mitochondrial structural disorganization, dysfunction of mitochondrial metabolism and subsequent oxidative stress mediated neurodegeneration
Summary
Mitochondria are essential organelles and mitochondrial dysfunction is frequently observed in neurodegenerative diseases and aging. Several studies have shown that release of endoplasmic reticulum (ER) Ca2+ results in the elevation of mitochondrial Ca2+ levels which in turn stimulates metabolic activity of the mitochondria (Das and Harris, 1990; Glancy and Balaban, 2012; Hansford and Zorov, 1998; McCormack and Denton, 1993; Mildaziene et al, 1995; Wernette et al, 1981). Insults or deregulated signaling between the ER and mitochondria can cause mitochondrial dysfunction and affect cellular fitness. Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and accounts for between 60–80% of all cases of dementia.
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