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.

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…Serum glucose, cholesterol, and phospholipids showed no significant difference between Clpp ‐deficient and WT mice at any time point, while triglycerides were significantly lower in 9 months old Clpp −/− mice ( p  <   0.01; Supporting Information Figure S2). To confirm the reported infertility of Clpp −/− female mice (Gispert et al., 2013), we conducted a continuous mating study using sexually mature female mice ( n  = 5 for each genotype) and WT male mice of proven fertility. After 12 weeks of mating, there were no pregnancies or deliveries observed in Clpp −/− female mice.…”

“…Transcriptional activation of mtUPR genes and translational suppression seem to be mediated by two parallel mechanisms, both requiring CLPP (Aldridge et al., 2007; Benedetti et al., 2006; Haynes et al., 2007; Zhao et al., 2002) and reviewed in (Jensen & Jasper, 2014; Schulz & Haynes, 2015). It is important that, recessive Clpp mutations have been identified in the human Perrault variant of ovarian failure and sensorineural hearing loss (Jenkinson et al., 2013), and global germline Clpp knockout mice display auditory deficits and complete female and male infertility, in addition to reduced pre/postnatal survival and marked ubiquitous growth retardation (Gispert et al., 2013). …”

“…In this study, we aimed to uncover the mechanisms leading to female infertility in mice with global germline deletion of Clpp (Gispert et al., 2013). We found that Clpp knockout ( Clpp −/− ) mice generate lower number of mature oocytes and two‐cell embryos and no blastocysts and that these deficiencies in oocyte and embryo development are associated with impaired mitochondrial function and dynamics.…”

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

“…The physiological importance of these proteolytic complexes is reflected in their requirement for the viability and/or virulence of some bacteria and the observation that loss-of-function mutations in mammals are linked to developmental defects and disease (2)(3)(4)(5)(6)(7)(8). Most well-characterized ClpP enzymes come from organisms that have a single clpP gene and consist of identical heptameric rings, which stack face-to-face to enclose a degradation chamber in which 14 active sites mediate peptide-bond hydrolysis (1,9,10).…”

Chaperones and Proteases of Mitochondria: From Protein Folding and Degradation to Mitophagy

“…Based on its close relation to the bacterial protease system, mtClpP is assumed to be involved in PQC functions in the matrix although no specific substrates are known so far. Very recently, a knockout model of mtClpP in mice was published, exhibiting pronounced growth retardation and failure of certain organ functions [107]. Another recent finding revealed that a knockdown of the corresponding chaperone component, mtClpX, resulted in alterations of mitochondrial nucleoid structure in human cells [108].…”