TY  - JOUR
A1  - Maletzko, Antonia
A1  - Key, Jana
A1  - Wittig, Ilka
A1  - Gispert, Suzana
A1  - Koepf, Gabriele
A1  - Canet Pons, Júlia
A1  - Torres-Odio, Sylvia
A1  - West, A. Phillip
A1  - Auburger, Georg
T1  - Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse
T2  - Neurogenetics
N2  - Mitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated 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 the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.
KW  - PRLTS3
KW  - Release of mtDNA and mtRNA
KW  - cGAS-STING
KW  - Leukodystrophy
KW  - Ataxia
KW  - Mitochondrial amino acid tRNA synthetases
KW  - TWINKLE
KW  - POLG
KW  - MTRNR1
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62600
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-626001
SN  - 1364-6753
N1  - Open access funding enabled and organized by Projekt DEAL. This research was supported mainly with internal funds of the Goethe University Frankfurt. IW was financed by a grant to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906D), by the Deutsche Forschungsgemeinschaft (DFG) (SFB 815/Z1), and by the Cardio Pulmonary Institute (CPI) of the DFG (EXC2026 and TRR267-Z02. P.W. and S.T-O. were supported by the Office of the Assistant Secretary of Defense for Health Affairs, US Department of Defense Awards W81XWH-17-1-0052 and W81XWH-20-1-0150 (to A.P.W.) through the Peer-Reviewed Medical Research Programs. Additional support was provided by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) Grant R01HL148153 (to A.P.W.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the NIH or the US Department of Defense.
VL  - 22
SP  - 297
EP  - 312
PB  - Springer
CY  - Berlin; Heidelberg
ER  -