Ablation of mitochondrial rhomboid Parl causes Leigh syndrome

ABSTRACT: The mitochondrial intramembrane rhomboid protease Parl plays essential roles in cell death but its physiological contribution remains unclear. In the present study we show that Parl ablation causes a dramatic necrotic neurodegeneration consistent with Leigh syndrome, a mitochondrial disease characterized by disrupted energy metabolism. Brain- but not liver or muscle- specific Parl deficient animals mimick Parl knock out animals. Deficiencies of the major substrates, Pink1, Pgam5, and of the complex III assembly factor Ttc19 are insufficient to modify or mimic the phenotype, suggesting that the mechanism involve a combination of Parl-/- induced effects. To investigate which mitochondrial protein changes could underlie the Parl-/- neurodegeneration we performed a quantitative mass spectrometry-based proteome analysis of brain mitochondria purified from three WT and three Parl-/- mice, leading to the quantification of 781 proteins annotated as mitochondrial resident in Swissprot. Statistical analysis revealed the accumulation or disappearance of Parl substrates, and following extensive validation, our data indicate that Pink1, Pgam5, Ttc19, Stard7, Diablo, and Clpb are genuine Parl substrates, and that Pink1, Pgam5, and Ttc19 are the most severely misprocessed substrates in brain. Together, alterations in the brain mitochondrial proteome of Parl-/- mice indicate defects in the ubiquinone pathway and complex III, which is confirmed by functional assays on neuronal mitochondria. Deficient processing of substrates by Parl leads to progressive loss of cristae structure, destabilization of electron transport, coenzyme Q deficiency, and mitochondrial calcium metabolism leading to Leigh syndrome.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Leigh Disease

SUBMITTER: Impens Francis  

LAB HEAD: Bart De Strooper

PROVIDER: PXD008908 | Pride | 2018-11-21

REPOSITORIES: pride