Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans.
Elife
; 72018 07 10.
Article
em En
| MEDLINE
| ID: mdl-29989545
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Cálcio
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Caenorhabditis elegans
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Doenças Neurodegenerativas
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Proteínas de Caenorhabditis elegans
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Proteínas de Membrana
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Mitocôndrias
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Mutação
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article