CLPP Depletion Causes Diplotene Arrest; Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2

Cells. 2022 Dec 22;12(1):52. doi: 10.3390/cells12010052.


Human Perrault syndrome (PRLTS) is autosomal, recessively inherited, and characterized by ovarian insufficiency with hearing loss. Among the genetic causes are mutations of matrix peptidase CLPP, which trigger additional azoospermia. Here, we analyzed the impact of CLPP deficiency on male mouse meiosis stages. Histology, immunocytology, different OMICS and biochemical approaches, and RT-qPCR were employed in CLPP-null mouse testis. Meiotic chromosome pairing and synapsis proceeded normally. However, the foci number of the crossover marker MLH1 was slightly reduced, and foci persisted in diplotene, most likely due to premature desynapsis, associated with an accumulation of the DNA damage marker γH2AX. No meiotic M-phase cells were detected. Proteome profiles identified strong deficits of proteins involved in male meiotic prophase (HSPA2, SHCBP1L, DMRT7, and HSF5), versus an accumulation of AURKAIP1. Histone H3 cleavage, mtDNA extrusion, and cGAMP increase suggested innate immunity activation. However, the deletion of downstream STING/IFNAR failed to alleviate pathology. As markers of underlying mitochondrial pathology, we observed an accumulation of PRLTS proteins ERAL1, PEO1, and HARS2. We propose that the loss of CLPP leads to the extrusion of mitochondrial nucleotide-binding proteins to cytosol and nucleus, affecting late meiotic prophase progression, and causing cell death prior to M-phase entry. This phenotype is more severe than in mito-mice or mutator-mice.

Keywords: H3K9ac; RMND1; Twinkle helicase; acSMC3; acetyl–tubulin; cGAS-STING signaling; homologous recombination; meiosis-I; pachytene–diplotene; tRNA/rRNA processing.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acyl-tRNA Synthetases* / genetics
  • Animals
  • Endopeptidase Clp / genetics
  • Humans
  • Male
  • Meiosis*
  • Meiotic Prophase I
  • Mice
  • Mitochondria
  • Mitochondrial Proteins / genetics
  • Mutation
  • Testis


  • Mitochondrial Proteins
  • HARS2 protein, human
  • Amino Acyl-tRNA Synthetases
  • ClpP protein, human
  • Endopeptidase Clp

Supplementary concepts

  • Gonadal dysgenesis XX type deafness