Dataset Information

Inactivity of peptidase ClpP causes primary accumulation of mitochondrial disaggregase ClpX with its interactors at the nucleoid and RNA granule

ABSTRACT: Mitochondrial matrix peptidase ClpP inactivating mutations in human cause an autosomal recessive Perrault syndrome variant (PRLTS3), characterized by ovarian failure with early sensorineural deafness, often followed by general neurodegeneration. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are main cellular consequences of ClpP mutations. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brain. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with POLDIP2 as nucleoid component, LRPPRC as mitochondrial poly(A) mRNA granule element, GFM1 (in mouse also GRSF1) as tRNA processing factors. Only in mouse, accumulated ClpX, GFM1 and GRSF1 appeared in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2 and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids, and show nucleoid enlargement in human as key consequence.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Perrault Syndrome

SUBMITTER: Nina Bach

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD029418 | Pride | 2022-01-19

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20200430_NB_ClpP_0006_III_F1.raw	Raw
	20200430_NB_ClpP_0006_III_F2.raw	Raw
	20200430_NB_ClpP_0006_III_F3.raw	Raw
	20200430_NB_ClpP_0006_III_F4.raw	Raw
	20200430_NB_ClpP_0006_III_F5.raw	Raw

Items per page:

1 - 5 of 66

Publications

Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA.

Key Jana J Torres-Odio Sylvia S Bach Nina C NC Gispert Suzana S Koepf Gabriele G Reichlmeir Marina M West A Phillip AP Prokisch Holger H Freisinger Peter P Newman William G WG Shalev Stavit S Sieber Stephan A SA Wittig Ilka I Auburger Georg G

Cells 20211129 12

Biallelic pathogenic variants in <i>CLPP</i>, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellu ...[more]

PMID: 34943861

Similar Datasets

Project description:The peptidase ClpP is conserved from bacteria to human. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder. Because of its known relevance for the mitochondrial unfolded protein response during cell stress, we characterized two ClpP knock-out mouse founder lines and documented similar phenotypes. Ubiquitously, ClpP absence led to accumulation of its interactor protein ClpX without transcript upregulation. Interestingly, most wild-type tissues with substantial ClpP amounts had no detectable ClpX. This inverse correlation suggests that ClpX levels and degradation are regulated by ClpP. The expectation of similar protein levels, in view of a reported association of heptameric ClpP rings with hexameric ClpX rings, was confirmed only in testis of wild-type animals. Germline tissue was exceptional also in its vulnerability to ClpP deletion, with both founder lines showing complete infertility for males and females. Otherwise, ubiquitous mitochondrial dysfunction was apparent from severe growth retardation and reduced spontaneous motor activity of the animals, and from a pronounced decrease in pre-/postnatal survival. Spermatogenesis was found aborted at the spermatid stage, acrosomes and axonemes were not formed. Overall, tissue-specific roles of ClpP were evident by this massive effect for germ cells, mild bioenergetic deficits in muscle and liver tissues, and excellent compensation in brain. ClpX was previously reported to chaperone unfolded proteins and also DNA condensation in mitochondria, so it is likely that this pathway is particularly susceptible in germ cells. In conclusion, our study indicates that the role of ClpP in quality control is indispensable during development for cells with rapid changes of mitochondrial numbers, and is relevant during aging for growth and survival of the organism. Factorial design comparing ClpP knock-out mice with wild type littermates in five different tissues (brain, testis, liver, skeletal and heart muscle)