VIB Center for Brain and Disease Research, 3000 Leuven, Belgium;
Department of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):277-286. doi: 10.1073/pnas.1811938116. Epub 2018 Dec 21.
The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome.
线粒体跨膜菱形蛋白酶 PARL 已被牵涉到多种体外功能，但它在体内的生理作用仍不清楚。在这里，我们展示了在小鼠中缺失会导致类似于 Leigh 综合征的坏死性脑脊髓病，这是一种以能量产生中断为特征的线粒体疾病。在神经系统中条件性缺乏 PARL 但在肌肉中不缺乏的小鼠，会发展出与生殖系 KO 相似的表型，这表明 PARL 在神经内稳态中起着至关重要的作用。对两个主要 PARL 底物 PINK1 和 PGAM5 的遗传修饰并不能修饰这种严重的神经表型。大脑线粒体受到进行性超微结构变化和复合物 III (CIII)活性、辅酶 Q (CoQ)生物合成以及线粒体钙代谢缺陷的影响。PARL 对于 TTC19 的稳定表达是必需的，TTC19 对于 CIII 活性是必需的，而 COQ4 对于 CoQ 生物合成是必不可少的。因此，PARL 在神经系统中线粒体呼吸链的维持中起着以前被忽视的组成性作用，其缺乏会导致进行性的线粒体功能障碍和结构异常，导致神经元坏死和 Leigh 样综合征。
