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PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Jan 02; Vol. 116 (1), pp. 277-286. Date of Electronic Publication: 2018 Dec 21. - Publication Year :
- 2019
-
Abstract
- 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 <superscript>- / -</superscript> 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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Brain metabolism
Calcium metabolism
Leigh Disease metabolism
Leigh Disease physiopathology
Liver metabolism
Male
Membrane Potential, Mitochondrial
Mice
Mice, Knockout
Mitochondria metabolism
Mitochondrial Encephalomyopathies metabolism
Mitochondrial Encephalomyopathies physiopathology
Muscle, Skeletal metabolism
Reactive Oxygen Species metabolism
Electron Transport Complex III metabolism
Leigh Disease etiology
Metalloproteases deficiency
Mitochondrial Proteins deficiency
Ubiquinone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 116
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 30578322
- Full Text :
- https://doi.org/10.1073/pnas.1811938116