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PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome.

Proc. Natl. Acad. Sci. U.S.A.2019 Jan 02;116(1):277-286. Epub 2018 Dec 21
Marco Spinazzi 1 , Enrico Radaelli 2 , Katrien Horré 1 , Amaia M Arranz 1 , Natalia V Gounko 3 , Patrizia Agostinis 4 , Teresa Mendes Maia 5 , Francis Impens 5 , Vanessa Alexandra Morais 6 , Guillermo Lopez-Lluch 7 , Lutgarde Serneels 1 , Placido Navas 7 , Bart De Strooper 8
Marco Spinazzi 1 , Enrico Radaelli 2 , Katrien Horré 1 , Amaia M Arranz 1 , Natalia V Gounko 3 , Patrizia Agostinis 4 , Teresa Mendes Maia 5 , Francis Impens 5 , Vanessa Alexandra Morais 6 , Guillermo Lopez-Lluch 7 , Lutgarde Serneels 1 , Placido Navas 7 , Bart De Strooper 8
+ et al

[No authors listed]

Author information
  • 1 Department of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
  • 2 Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051.
  • 3 Electron Microscopy Platform, VIB Bio Imaging Core, 3000 Leuven, Belgium.
  • 4 Cell Death Research & Therapy Laboratory, Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
  • 5 Department for Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
  • 6 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
  • 7 Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 8 UK Dementia Research Institute, University College London, WC1E 6BT London, United Kingdom.

摘要

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 Parl 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 Parl 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. Parl-- 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.

KEYWORDS: Leigh syndrome, mitochondria, neurodegeneration, respiratory chain, rhomboid protease

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