TY - JOUR T1 - Parl Deficiency in Mouse Causes Coenzyme Q Depletion, Complex III Defects, and Leigh-like Syndrome JF - bioRxiv DO - 10.1101/368654 SP - 368654 AU - Marco Spinazzi AU - Enrico Radaelli AU - Katrien Horré AU - Amaia M. Arranz AU - Natalia Gounko AU - Patrizia Agostinis AU - Francis Impens AU - Vanessa Alexandra Morais AU - Guillermo Lopez-Lluch AU - Lutgarde Serneels AU - Placido Navas AU - Bart De Strooper Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/07/13/368654.abstract N2 - 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 striking 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 knockouts 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 defects in Complex III activity and in coenzyme Q biosynthesis. Parl is necessary for the stable expression of Ttc19, required for Complex III activity, and of Coq4, essential in coenzyme Q biosynthesis. Thus, Parl plays a previously overseen constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and Leigh-like syndrome. ER -