Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
Institute for Mitochondrial Diseases and Ageing, Medical Faculty and Center for Molecular Medicine Cologne (CMMC), D-50931 Cologne, Germany.
Brain. 2022 Mar 29;145(1):92-104. doi: 10.1093/brain/awab303.
Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. Therefore, it is not surprising that mutations in either mtDNA or nuclear DNA-encoded genes of mitochondrial proteins cause diseases affecting the oxidative phosphorylation system, which are heterogeneous from a clinical, genetic, biochemical and molecular perspective and can affect patients at any age. Despite all this, it is surprising that our understanding of the mechanisms governing mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored. We recently showed that loss of the mitochondrial matrix protease caseinolytic protease proteolytic subunit (CLPP) ameliorates phenotypes in cells characterized by defects in oxidative phosphorylation maintenance. Here, we build upon this finding by showing that CLPP depletion is indeed beneficial in vivo for various types of neuronal populations, including Purkinje cells in the cerebellum and cortical and hippocampal neurons in the forebrain, as it strongly improves distinct phenotypes of mitochondria encephalopathy, driven by the deficiency of the mitochondrial aspartyl tRNA synthase DARS2. In the absence of CLPP, neurodegeneration of DARS2-deficient neurons is delayed as they present milder oxidative phosphorylation dysfunction. This in turn leads to a decreased neuroinflammatory response and significantly improved motor functions in both double-deficient models (Purkinje cell-specific or forebrain neuron-specific Dars2/Clpp double knockout mice). We propose that diminished turnover of respiratory complex I caused by the loss of CLPP is behind the improved phenotype in Dars2/Clpp double knockout animals, even though this intervention might not restore respiratory complex I activity but rather improve mitochondrial cristae morphology or help maintain the NAD+/NADH ratio inside mitochondria. These results also open the possibility of targeting CLPP activity in many other mitochondrial encephalopathies characterized by respiratory complex I instability.
线粒体是真核细胞中普遍存在的必需细胞器，其作用是将食物转化为可用能量。因此，无论是 mtDNA 还是核 DNA 编码的线粒体蛋白基因发生突变，都会导致影响氧化磷酸化系统的疾病，这从临床、遗传、生化和分子角度来看都是多种多样的，并且可以影响任何年龄段的患者。尽管如此，令人惊讶的是，我们对调控线粒体基因表达及其相关疾病的机制的理解仍然很肤浅，治疗干预也在很大程度上尚未得到探索。我们最近表明，缺失线粒体基质蛋白酶解聚酶（CLPP）可以改善氧化磷酸化维持缺陷的细胞中的表型。在这里，我们通过证明 CLPP 的耗竭实际上对各种类型的神经元群体有益，包括小脑的浦肯野细胞和前脑的皮质和海马神经元，进一步证实了这一发现，因为它可以强烈改善由线粒体天冬氨酸 tRNA 合成酶 DARS2 缺乏引起的线粒体脑病的不同表型。在缺乏 CLPP 的情况下，DARS2 缺陷神经元的神经退行性变被延迟，因为它们表现出较轻的氧化磷酸化功能障碍。这反过来又导致神经炎症反应减少，并且在双缺失模型（浦肯野细胞特异性或前脑神经元特异性 Dars2/Clpp 双敲除小鼠）中运动功能显著改善。我们提出，由于 CLPP 的缺失导致呼吸复合物 I 的周转率降低，是 Dars2/Clpp 双敲除动物表型改善的原因，尽管这种干预可能不会恢复呼吸复合物 I 的活性，而是改善线粒体嵴形态或有助于维持线粒体内部的 NAD+/NADH 比例。这些结果还为靶向许多其他以呼吸复合物 I 不稳定为特征的线粒体脑病中的 CLPP 活性开辟了可能性。
