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Key, J.* ; Torres-Odio, S.* ; Bach, N.C.* ; Gispert, S.* ; Koepf, G.* ; Reichlmeir, M.* ; West, A.P.* ; Prokisch, H. ; Freisinger, P.* ; Newman, W.G.* ; Shalev, S.* ; Sieber, S.A.* ; Wittig, I.* ; Auburger, G.*

Inactivity of peptidase clpp causes primary accumulation of mitochondrial disaggregase clpx with its interacting nucleoid proteins, and of mtdna.

Cells 10:3354 (2021)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Biallelic pathogenic variants in CLPP, 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 pro-gressive neurological deficits. Mouse models showed that accumulations of (i) its main protein in-teractor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. 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 brains. Validation work included novel ClpP-mutant patient fi-broblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear 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 a key consequence.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ataxia ; Clpb ; Eral1 ; Hars2 ; Lars2 ; Leukodystrophy ; Parkinson’s Disease ; Twnk; Methylmalonyl-coa Mutase; Crystal-structure; Rna Granules; Complex; Specificity; Twinkle; Identification; Infertility; Expression; Mutations
ISSN (print) / ISBN 2073-4409
e-ISSN 2073-4409
Zeitschrift Cells
Quellenangaben Band: 10, Heft: 12, Seiten: , Artikelnummer: 3354 Supplement: ,
Verlag MDPI
Verlagsort Basel
Nichtpatentliteratur Publikationen
Institut(e) Institute of Neurogenomics (ING)
Förderungen NHLBI NIH HHS
Office of the Assistant Secretary for Health
Action Medical Research
German Network for Mitochondrial Disorders