title: Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors.
abstract: The caseinolytic peptidase P (CLPP) is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of CLPP null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction.
authors.affiliation: Experimental Neurology.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Dajana
authors.initials: D
authors.lastname: Parganlija
authors.forename: Michael
authors.initials: M
authors.lastname: Klinkenberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Pawel
authors.initials: P
authors.lastname: Grzmil
authors.forename: Sebastian
authors.initials: S
authors.lastname: Koob
authors.forename: Andrea
authors.initials: A
authors.lastname: Hamann
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Finja
authors.initials: F
authors.lastname: Büchel
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabé de Angelis
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Reichert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.forename: Heinz D
authors.initials: HD
authors.lastname: Osiewacz
authors.forename: Marina
authors.initials: M
authors.lastname: Jendrach
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004195:Disease Models, Animal; D049071:Endopeptidase Clp / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D023061:Gene Order; D006066:Gonads / Q000378:metabolism / Q000473:pathology; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism; D007246:Infertility / Q000235:genetics* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D018836:Inflammation Mediators; D018832:Molecular Chaperones; C000589752:CLPP protein, mouse; D049071:Endopeptidase Clp; C000589753:CLPX protein, mouse