PXD033388

PXD033388 is an original dataset announced via ProteomeXchange.

Title	ClpP-deletion causes azoospermia, with meiosis-I delay and insufficient biosynthesis of spermatid factors, due to mitochondrial dysfunction with accumulation of Perrault proteins ERAL1, PEO1, and HARS2.
Description	Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, as antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator mice.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:42:39.827.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Aneesha Kohli
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-23 15:27:51	ID requested
1	2023-03-11 04:27:11	announced
⏵ 2	2023-11-14 08:42:48	announced	2023-11-14: Updated project metadata.

Key J, Gispert S, Koornneef L, Sleddens-Linkels E, Kohli A, Torres-Odio S, Koepf G, Amr S, Reichlmeir M, Harter PN, West AP, M, ü, nch C, Baarends WM, Auburger G, CLPP Depletion Causes Diplotene Arrest

Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2. Cells, 12(1):(2022) [pubmed]

submitter keyword: meiosis-I

zygotene-pachytene

homologous recombination

H3K9ac

acetyl-tubulin

Twinkle helicase

RMND1

tRNA /rRNA processing

cGAS-STING signaling

Christian Münch
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; Cardio-Pulmonary Institute, Frankfurt am Main, Germany
contact email	ch.muench@em.uni-frankfurt.de
lab head
Aneesha Kohli
contact affiliation	Institute of Biochemistry II, Goethe University, Frankfurt am Main
contact email	aneeshak19@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD033388
     1. Label: PRIDE project
     2. Name: ClpP-deletion causes azoospermia, with meiosis-I delay and insufficient biosynthesis of spermatid factors, due to mitochondrial dysfunction with accumulation of Perrault proteins ERAL1, PEO1, and HARS2.