ClpP-Deletion Causes Azoospermia, with Meiosis-I Delay and Insufficient Biosynthesis of Spermatid Factors, Due to Mitochondrial Dysfunction with Accumulation of Perrault Proteins ERAL1, PEO1, and HARS2 Institutional Repository Document uri icon


  • Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, among antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator-mice.

altmetric score

  • 0.25

author list (cited authors)

  • Gispert, S., Key, J., Kohli, A., Torres-Odio, S., Koepf, G., Amr, S., ... Auburger, G.

citation count

  • 1

complete list of authors

  • Gispert, Suzana||Key, Jana||Kohli, Aneesha||Torres-Odio, Sylvia||Koepf, Gabriele||Amr, Shady||Reichlmeir, Marina||Harter, Patrick N||West, A Phillip||M√ľnch, Christian||Auburger, Georg

Book Title


publication date

  • April 2022