PXD008908-2

PXD008908 is an original dataset announced via ProteomeXchange.

Title	Ablation of mitochondrial rhomboid Parl causes Leigh syndrome
Description	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.
HostingRepository	PRIDE
AnnounceDate	2018-11-21
AnnouncementXML	Submission_2019-02-26_07:54:52.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Impens Francis
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2018-02-09 05:32:47	ID requested
1	2018-11-21 02:52:14	announced
⏵ 2	2019-02-26 07:54:54	announced	Updated publication reference for PubMed record(s): 30578322.
3	2024-10-22 04:42:57	announced	2024-10-22: Updated project metadata.

Spinazzi M, Radaelli E, Horr, é K, Arranz AM, Gounko NV, Agostinis P, Maia TM, Impens F, Morais VA, Lopez-Lluch G, Serneels L, Navas P, De Strooper B, PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome. Proc Natl Acad Sci U S A, 116(1):277-286(2019) [pubmed]

curator keyword: Biological

submitter keyword: PARL, rhomboids, neurodegeneration, Leigh syndrome, proteolysis, necrosis, apoptosis, TTC19, PINK1, PGAM5, Complex III

Bart De Strooper
contact affiliation	VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
contact email	bart.destrooper@kuleuven.vib.be
lab head
Impens Francis
contact affiliation	VIB Proteomics Expertise Center
contact email	francis.impens@vib-ugent.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008908
     1. Label: PRIDE project
     2. Name: Ablation of mitochondrial rhomboid Parl causes Leigh syndrome