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Activation of NF-κB signaling via cytosolic mitochondrial RNA sensing in kerotocytes with mitochondrial DNA common deletion
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).ORCID iD: 0000-0002-1617-334X
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Section of Physiotherapy.ORCID iD: 0000-0002-6091-3982
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.ORCID iD: 0000-0002-7906-9152
2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 7360Article in journal (Refereed) Published
Abstract [en]

Scar formation as a result of corneal wound healing is a leading cause of blindness. It is a challenge to understand why scar formation is more likely to occur in the central part of the cornea as compared to the peripheral part. The purpose of this study was to unravel the underlying mechanisms. We applied RNA-seq to uncover the differences of expression profile in keratocytes in the central/peripheral part of the cornea. The relative quantity of mitochondrial RNA was measured by multiplex qPCR. The characterization of mitochondrial RNA in the cytoplasm was confirmed by immunofluoresence microscope and biochemical approach. Gene expression was analyzed by western blot and RT qPCR. We demonstrate that the occurrence of mitochondrial DNA common deletion is greater in keratocytes from the central cornea as compared to those of the peripheral part. The keratocytes with CD have elevated oxidative stress levels, which leads to the leakage of mitochondrial double-stranded RNA into the cytoplasm. The cytoplasmic mitochondrial double-stranded RNA is sensed by MDA5, which induces NF-κB activation. The NF-κB activation thereafter induces fibrosis-like extracellular matrix expressions and IL-8 mRNA transcription. These results provide a novel explanation of the different clinical outcome in different regions of the cornea during wound healing.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021. Vol. 11, no 1, article id 7360
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
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URN: urn:nbn:se:umu:diva-182367DOI: 10.1038/s41598-021-86522-6ISI: 000636796200002PubMedID: 33795727Scopus ID: 2-s2.0-85103674533OAI: oai:DiVA.org:umu-182367DiVA, id: diva2:1547418
Available from: 2021-04-26 Created: 2021-04-26 Last updated: 2023-10-18Bibliographically approved

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Zhou, XinBackman, Ludvig J.Danielson, Patrik

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