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

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 character...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 1; pp. 277 - 286
Main Authors:	Spinazzi, Marco, Radaelli, Enrico, Horré, Katrien, Arranz, Amaia M., Gounko, Natalia V., Agostinis, Patrizia, Maia, Teresa Mendes, Impens, Francis, Moraisi, Vanessa Alexandra, Lopez-Lluch, Guillermo, Serneels, Lutgarde, Navas, Placido, De Strooper, Bart
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 02-01-2019
Series:	PNAS Plus
Subjects:	Ablation Abnormalities Animals Biological Sciences Biosynthesis Brain Brain - metabolism Calcium Calcium (mitochondrial) Calcium - metabolism Coenzyme Q Defects Depletion Electron transport Electron Transport Complex III - metabolism Genetic modification Homeostasis Human health and pathology Leigh Disease - etiology Leigh Disease - metabolism Leigh Disease - physiopathology Leigh-like syndrome Life Sciences Liver - metabolism Male Membrane Potential, Mitochondrial Metabolism Metalloproteases - deficiency Mice Mice, Knockout Mitochondria Mitochondria - metabolism Mitochondrial Encephalomyopathies - metabolism Mitochondrial Encephalomyopathies - physiopathology Mitochondrial Proteins - deficiency Muscle, Skeletal - metabolism Muscles Necrosis Nervous system Neurodegeneration Phenotypes PNAS Plus PTEN-induced putative kinase Reactive Oxygen Species - metabolism Rodents Substrates Ubiquinone - metabolism rhomboid protease neurodegeneration Leigh syndrome mitochondria respiratory chain Metalloproteases Brain Mitochondrial Encephalomyopathies Reactive Oxygen Species Calcium Mitochondrial Liver Male Leigh Disease Mitochondrial Proteins Membrane Potential Knockout Skeletal Animals Ubiquinone Mice Muscle Electron Transport Complex III
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23 PMCID: PMC6320509 Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved November 21, 2018 (received for review July 11, 2018) Author contributions: M.S., L.S., P.N., and B.D.S. designed research; M.S., E.R., K.H., A.M.A., N.V.G., F.I., V.A.M., and G.L.-L. performed research; P.A. contributed new reagents/analytic tools; M.S., E.R., K.H., A.M.A., T.M.M., F.I., G.L.-L., L.S., P.N., and B.D.S. analyzed data; M.S. and B.D.S. wrote the paper; and P.A. provided critical feedback.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1811938116