CLPP Depletion Causes Diplotene Arrest; Underlying Testis Mitochondrial Dysfunction Occurs with Accumulation of...

Area of Science:

• Reproductive Biology
• Mitochondrial Biology
• Genetics

Background:

• Perrault syndrome (PRLTS) is an autosomal recessive disorder causing ovarian insufficiency and hearing loss.
• Mutations in CLPP, a matrix peptidase, are a known genetic cause of PRLTS, also linked to male infertility (azoospermia).

Purpose of the Study:

• To investigate the impact of CLPP deficiency on male mouse meiosis.
• To elucidate the molecular mechanisms underlying CLPP-related male infertility.

Main Methods:

• Histology and immunocytology of CLPP-null mouse testis.
• OMICS (proteomics) and biochemical analyses.
• RT-qPCR for gene expression analysis.

Main Results:

• Normal meiotic chromosome pairing and synapsis, but reduced MLH1 foci and persistent foci suggesting premature desynapsis.
• Accumulation of DNA damage marker γH2AX and absence of meiotic M-phase cells.
• Deficits in key meiotic prophase proteins (HSPA2, SHCBP1L, DMRT7, HSF5) and accumulation of AURKAIP1.
• Evidence of innate immunity activation (histone H3 cleavage, mtDNA extrusion, cGAMP increase), not alleviated by STING/IFNAR deletion.
• Accumulation of PRLTS-associated mitochondrial proteins (ERAL1, PEO1, HARS2).

Conclusions:

• CLPP loss causes mitochondrial protein extrusion into the cytosol and nucleus, disrupting late meiotic prophase progression.
• This leads to cell death before M-phase entry, presenting a severe phenotype potentially linked to mitochondrial pathology.
• The findings offer insights into the pathogenesis of CLPP-related male infertility and Perrault syndrome.