Presenilin mutations deregulate mitochondrial Ca 2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans .
| Autor: | Sarasija S; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States., Laboy JT; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States., Ashkavand Z; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States., Bonner J; Department of Biology, Skidmore College, Saratoga Springs, United States., Tang Y; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States., Norman KR; Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ELife [Elife] 2018 Jul 10; Vol. 7. Date of Electronic Publication: 2018 Jul 10. |
| DOI: | 10.7554/eLife.33052 |
| Abstrakt: | 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 Ca 2+ signaling leads to an increase in mitochondrial Ca 2+ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca 2+ release, mitochondrial Ca 2+ 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 Ca 2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases. Competing Interests: SS, JL, ZA, JB, YT, KN No competing interests declared (© 2018, Sarasija et al.) |
| Databáze: | MEDLINE |
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