Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
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DOI：
10.1038/s41467-023-38501-w
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发表时间：
2023-05-24
影响因子：
16.6
通讯作者：
Annaert, Wim
中科院分区：
文献类型：
--
作者：
Van Acker, Zoe P.;Perdok, Anika;Hellemans, Ruben;North, Katherine;Vorsters, Inge;Cappel, Cedric;Dehairs, Jonas;Swinnen, Johannes V.;Sannerud, Ragna;Bretou, Marine;Damme, Markus;Annaert, Wim
磷脂酶 D3 (PLD3) 多态性与迟发性阿尔茨海默病 (LOAD) 相关。作为一种溶酶体 5'-3' 核酸外切酶，其神经元底物以及缺陷的溶酶体核苷酸分解代谢如何与 AD 蛋白病相关仍然未知。我们确定线粒体 DNA (mtDNA) 是主要的生理底物，并显示其在 PLD3 缺陷细胞的溶酶体中明显的积聚。 mtDNA 积累产生了一个降解（蛋白水解）瓶颈，在超微结构水平上表现为显着丰富的多层体，通常含有线粒体残余物，这与 PINK1 依赖性线粒体自噬的增加相关。 mtDNA 溶酶体渗漏至细胞质，激活 cGAS-STING 信号传导，上调自噬并诱导淀粉样蛋白前体 C 末端片段 (APP-CTF) 和胆固醇积累。 STING 抑制在很大程度上使 APP-CTF 水平正常化，而 PLD3 缺陷背景中的 APP 敲除会降低 STING 激活并使胆固醇生物合成正常化。总的来说，我们通过溶酶体核苷酸周转、cGAS-STING 和 APP 代谢之间的前馈环证明了分子串扰，当失调时，会导致神经元内溶酶体死亡，如 LOAD 中观察到的。磷脂酶 D3 多态性与迟发性阿尔茨海默病有关，但其机制尚不清楚。 Van Acker 及其同事表明，磷脂酶 D3 处理溶酶体中的线粒体 DNA，以维持溶酶体稳态和淀粉样前体蛋白的适当降解。
Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer’s disease (LOAD). Being a lysosomal 5’-3’ exonuclease, its neuronal substrates remained unknown as well as how a defective lysosomal nucleotide catabolism connects to AD-proteinopathy. We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates a degradative (proteolytic) bottleneck that presents at the ultrastructural level as a marked abundance of multilamellar bodies, often containing mitochondrial remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage of mtDNA to the cytosol activates cGAS–STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout in PLD3-deficient backgrounds lowers STING activation and normalizes cholesterol biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between lysosomal nucleotide turnover, cGAS-STING and APP metabolism that, when dysregulated, result in neuronal endolysosomal demise as observed in LOAD. Phospholipase D3 polymorphisms are linked to late-onset Alzheimer’s disease but the mechanisms are not understood. Van Acker and colleagues show that Phospholipase D3 processes mitochondrial DNA in lysosomes to maintain lysosomal homeostasis and proper degradation of the amyloid precursor protein.
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影响因子：
15.9
作者：
Cisneros J;Belton TB;Shum GC;Molakal CG;Wong YC
通讯作者：
Wong YC
DOI：
10.1083/jcb.202009128
发表时间：
2020-12-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fischer TD;Wang C;Padman BS;Lazarou M;Youle RJ
通讯作者：
Youle RJ
影响因子：
5.8
作者：
Bus C;Zizmare L;Feldkaemper M;Geisler S;Zarani M;Schaedler A;Klose F;Admard J;Mageean CJ;Arena G;Fallier-Becker P;Ugun-Klusek A;Maruszczak KK;Kapolou K;Schmid B;Rapaport D;Ueffing M;Casadei N;Krüger R;Gasser T;Vogt Weisenhorn DM;Kahle PJ;Trautwein C;Gloeckner CJ;Fitzgerald JC
通讯作者：
Fitzgerald JC
DOI：
10.1016/j.bbalip.2010.05.010
发表时间：
2010-08-01
影响因子：
4.8
作者：
Cossec, Jack-Christophe;Simon, Anne;Potier, Marie-Claude
通讯作者：
Potier, Marie-Claude
影响因子：
6.1
作者：
Anand, Nikhita;Holcom, Angelina;Chamoli, Manish
通讯作者：
Chamoli, Manish