线粒体α-酮戊二酸脱氢酶失调导致chchd2相关帕金森病模型中脂质过氧化升高

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Ge Gao, Yong Shi, Han-Xiang Deng, Dimitri Krainc
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引用次数: 0

摘要

线粒体功能失调与帕金森病(PD)有关,但线粒体代谢在疾病发病机制中的作用仍有待阐明。通过对纯化线粒体的无偏倚代谢组学分析,我们发现了pd相关CHCHD2蛋白缺失后α-酮戊二酸脱氢酶(KGDH)途径的改变。KGDH是三羧酸循环中的一种限速酶复合物,在chchd2缺陷的雄性小鼠大脑和人类多巴胺能神经元中降低。KGDH缺乏导致α-酮戊二酸升高和脂质过氧化增加。硫辛酸(一种KGDH辅助因子和抗氧化剂)处理chchd2缺失的多巴胺能神经元,导致脂质过氧化和磷酸化α-突触核蛋白水平降低。CHCHD10是CHCHD2的近亲,主要与肌萎缩性侧索硬化症/额颞叶痴呆有关,不影响KGDH途径或脂质过氧化。总之,这些结果确定KGDH代谢途径是纠正帕金森病中脂质过氧化和α-突触核蛋白增加的可靶向线粒体机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson’s disease models

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson’s disease models

Dysregulation of mitochondrial function has been implicated in Parkinson’s disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson’s disease.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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