Loss of mitochondrial peptidase ClpP leads to upregulation of inflammatory factors in brain and embryonal fibroblasts of mice

The combination of premature ovarian failure and age-associated hearing deafness, inherited in autosomal recessive manner, was named Perrault syndrome. It may be caused by mutations in HSD17B4, HARS2, LARS2, PSMC3IP, C10orf2, CLPP and in un-identified genes. CLPP is a mitochondrial matrix peptidase that is crucial for the unfolded protein response of mitochondria (mtUPR). In a study of Clpp-/- mice we found the Perrault phenotype, but also loss of spermatids, growth retardation and anti-microbial protection. An accumulation of CLPX protein and mitochondrial DNA was accompanied by widespread induction of inflammatory mRNAs in several tissues (Gispert 2013 HMG). Now we tried to elucidate the age-associated hearing loss. Preliminary analyses of DPOAE (distortion product optoacoustic emissions) showed no response above 20000 Hz. Preliminary studies of acoustic startle responses showed a maximal deficit already at an age of 12 months. To understand mtUPR-triggered neurotoxicity at molecular level, we analyzed brain tissue with global proteomics. Elevated levels of inflammatory factors downstream the transcription factor STAT1 were prominent. STAT1 induction was also documented in murine embryonal fibroblasts. Thus, the innate immune system is triggered by the mitochondrial matrix protein degradation deficit due to CLPP deletion.