Prominent Increases of Nuclear DNAJA3and Cytosolic STAT1 with Nucleic Acid Sensors Underlie Innate Immunity Activation in ClpP-null Mouse Institutional Repository Document uri icon


  • Mitochondrial dysfunctions, e.g. abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy, activate innate immunity. Recent reports also showed that deletion of mitochondrial matrix peptidase ClpP in mice transcriptionally upregulates inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, immunoblots, and reverse transcriptase polymerase chain reaction. Anomalies in the mitochondrial unfolded protein responses pathway were prominent for the co-chaperone DNAJA3, and for its known interactor STAT1. Their mitochondrial dysregulation affected also their extra-mitochondrial abundance, as possible innate immune modulators. Increased expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). They can be explained by the accumulation of mitoribosomes and mitochondrial nucleoids in ClpP-null cells, which may act as damage-associated molecular patterns. The consistent dysregulation of these factors from early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

altmetric score

  • 0.25

author list (cited authors)

  • Maletzko, A., Key, J., Wittig, I., Gispert, S., Koepf, G., Canet-Pons, J., ... Auburger, G.

citation count

  • 0

complete list of authors

  • Maletzko, Antonia||Key, Jana||Wittig, Ilka||Gispert, Suzana||Koepf, Gabriele||Canet-Pons, JĂșlia||Torres-Odio, Sylvia||West, A Phillip||Auburger, Georg

Book Title


publication date

  • May 2021