Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.
Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.
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由于早老素丢失导致的线粒体钙处理的放松调节扰乱了氧化还原稳态，并促进了神经元功能障碍。
DOI：
10.3390/antiox11091642
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发表时间：
2022-08-24
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影响因子：
--
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中科院分区：
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--
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线粒体功能障碍和氧化应激是包括阿尔茨海默病(AD)在内的神经退行性疾病的主要病理生理学因素。然而，导致线粒体功能障碍和氧化应激的机制尚不清楚。家族性AD(FAD)是一种早发性AD，主要由早老素编码基因突变引起。以前，我们以秀丽线虫为模型系统来研究早老素功能，我们发现线虫早老素同源基因SEL-12的缺失会导致线粒体和胞浆钙水平的升高。在这里，我们提供的证据表明，在sel-12突变体中，神经元线粒体产生的活性氧物种(ROS)的升高和随后的神经变性是线粒体钙水平增加的结果，而不是细胞内钙水平的增加。我们还发现mTORC1信号是在sel-12突变体中维持高ROS的关键因素，部分是通过它对ROS清除系统SKN-1/NRF的抑制。我们的研究表明，SEL-12/早老素的丢失通过增加线粒体ROS的生成和上调mTORC1信号来扰乱神经元ROS的动态平衡，从而通过抑制SKN-1/NRF的抗氧化活性来加剧这种失衡。
Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.
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影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
5
作者：
Dai, Chongshan;Ciccotosto, Giuseppe D.;Xiao, Xilong
通讯作者：
Xiao, Xilong
影响因子：
48
作者：
Gutscher, Marcus;Pauleau, Anne-Laure;Dick, Tobias P.
通讯作者：
Dick, Tobias P.
DOI：
10.1073/pnas.90.24.12045
发表时间：
1993-12-15
影响因子：
11.1
作者：
DAIGLE, I;LI, C
通讯作者：
LI, C
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D