LONP1 is an ATP-dependent protease and chaperone that plays multiple vital roles in mitochondria. LONP1 is essential for mitochondrial homeostasis due to its role in maintenance of the mitochondrial genome and its central role in regulating mitochondrial processes such as oxidative phosphorylation, mitophagy, and heme biosynthesis. Bi-allelic LONP1 mutations have been reported to cause a constellation of clinical presentations. We report a patient heterozygous for a de novo mutation in LONP1: c.901C>T,p.R301W presenting as a neonate with seizures, encephalopathy, pachygyria and microcephaly. Assays of respiratory chain activity in muscle showed complex II-III function at 8% of control. Functional studies in patient fibroblasts showed a signature of dysfunction that included significant decreases in known proteolytic targets of LONP1 (TFAM, PINK1, phospho-PDH E1α) as well as loss of mitochondrial ribosome subunits MRPL44 and MRPL11 with concomitant decreased activity and level of protein subunits of oxidative phosphorylation complexes I and IV. These results indicate excessive LONP1 proteolytic activity and a loss of LONP1 chaperone activity. Further, we demonstrate that the LONP1 N-terminal domain is involved in hexamer stability of LONP1 and that the ability to make conformational changes is necessary for LONP1 to regulate proper functioning of both its proteolytic and chaperone activities.

中文翻译：

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LONP1 de novo 显性突变导致线粒体脑病，LONP1 分子伴侣活性丧失和 LONP1 蛋白水解活性过度

LONP1 是一种 ATP 依赖性蛋白酶和分子伴侣，在线粒体中发挥多种重要作用。由于 LONP1 在维持线粒体基因组中的作用及其在调节线粒体过程（如氧化磷酸化、线粒体自噬和血红素生物合成）中的核心作用，LONP1 对线粒体稳态至关重要。据报道，双等位基因 LONP1 突变会导致一系列临床表现。我们报告了 LONP1 从头突变的患者杂合子：c.901C>T,p.R301W 表现为新生儿癫痫发作、脑病、肿块和小头畸形。肌肉中呼吸链活动的测定显示复合物 II-III 功能为对照的 8%。对患者成纤维细胞的功能研究显示出功能障碍的特征，包括 LONP1 的已知蛋白水解靶标（TFAM、PINK1、磷酸化 PDH E1α) 以及线粒体核糖体亚基 MRPL44 和 MRPL11 的丢失，伴随着氧化磷酸化复合物 I 和 IV 的活性和蛋白质亚基水平的降低。这些结果表明过度的 LONP1 蛋白水解活性和 LONP1 分子伴侣活性的丧失。此外，我们证明 LONP1 N 端结构域参与 LONP1 的六聚体稳定性，并且使构象变化的能力对于 LONP1 调节其蛋白水解和分子伴侣活动的正常功能是必要的。这些结果表明过度的 LONP1 蛋白水解活性和 LONP1 分子伴侣活性的丧失。此外，我们证明 LONP1 N 端结构域参与 LONP1 的六聚体稳定性，并且使构象变化的能力对于 LONP1 调节其蛋白水解和分子伴侣活动的正常功能是必要的。这些结果表明过度的 LONP1 蛋白水解活性和 LONP1 分子伴侣活性的丧失。此外，我们证明 LONP1 N 端结构域参与 LONP1 的六聚体稳定性，并且使构象变化的能力对于 LONP1 调节其蛋白水解和分子伴侣活动的正常功能是必要的。