Loss of succinyl-CoA synthase ADP-forming beta subunit disrupts mtDNA stability and mitochondrial dynamics in neurons

作者

Zhao, YJ;Tian, J;Sui, SM;Yuan, XD;Chen, H;Qu, CQ;Du, YF;Guo, L;Du, H

作者单位

[Zhao, Yujun; Sui, Shaomei; Yuan, Xiaodong; Du, Heng] Shandong Univ, Shandong Qianfoshan Hosp, Jinan, Shandong, Peoples R China.;-;[Zhao, Yujun] Yantai Yuhuangding Hosp, Yantai, Shandong Sheng, Peoples R China.;-;[Tian, Jing; Sui, Shaomei; Chen, Hao; Guo, Lan; Du, Heng] Univ Texas Dallas, Richardson, TX 75083 USA.;-;[Yuan, Xiaodong] Jinan Cent Hosp, Jinan, Shandong Sheng, Peoples R China.;-;[Qu, Chuanqiang; Du, Yifeng] Shandong Univ, Shandong Prov Hosp, Jinan, Shandong Sheng, Peoples R China.

摘要

Succinyl Coenzyme A synthetase (SCS) is a key mitochondrial enzyme. Defected SCS ADP-forming beta subunit (SCS A-beta) is linked to lethal infantile Leigh or leigh-like syndrome. However, the impacts of SCS A-beta deficiency on mitochondria specifically in neurons have not yet been comprehensively investigated. Here, by down-regulating the expression levels of SCS A-beta in cultured mouse neurons, we have found that SCS A-beta deficiency induces severe mitochondrial dysfunction including lowered oxidative phosphorylation (OXPHOS) efficiency, increased mitochondrial superoxide production, and mtDNA depletion as well as aberrations of mitochondrial fusion and fission proteins, which eventually leads to neuronal stress. Our data also suggest that the deregulation of mitochondrial nucleoside diphosphate kinase (NDPK) together with defects in mitochondrial transcription factors including mitochondrial DNA pol gamma and Twinkle contribute to SCS A-beta deficiency-mediated mtDNA instability. Furthermore, we have found that SCS A-beta deficiency has detrimental influence on neuronal mitochondrial dynamics. Put together, the results have furnished our knowledge on the pathogenesis of SCS A-beta deficiency-related mitochondrial diseases and revealed the vital role of SCS A-beta in maintaining neuronal mitochondrial quality control and neuronal physiology.

关键词

ALZHEIMERS-DISEASE; LIGASE DEFICIENCY; MAMMALIAN-CELLS; PROTEIN DLP1; SYNTHETASES; EXPRESSION; MUTATIONS; DEPLETION; FISSION; FUSION

基本信息

所属机构:

归属医师: 杜怡峰屈传强

PMID：28769029

UT：000406816300042

刊名:SCIENTIFIC REPORTS

年，卷(期):2017年7卷

DOI：10.1038/s41598-017-05168-5

附件： pdf

收录: SCIE