Published May 3, 2021 - More info
Chronic inflammation is a pathologic feature of neurodegeneration and aging; however, the mechanism regulating this process is not understood. Melatonin, an endogenous free radical scavenger synthesized by neuronal mitochondria, decreases with aging and neurodegeneration. We proposed that insufficient melatonin levels impair mitochondrial homeostasis, resulting in mitochondrial DNA (mtDNA) release and activation of cytosolic DNA-mediated inflammatory response in neurons. We found increased mitochondrial oxidative stress and decreased mitochondrial membrane potential, with higher mtDNA release in brain and primary cerebro-cortical neurons of melatonin-deficient aralkylamine N-acetyltransferase (AANAT) knockout mice. Cytosolic mtDNA activated the cGAS/STING/IRF3 pathway, stimulating inflammatory cytokine generation. We found that Huntington’s disease mice had increased mtDNA release, cGAS activation, and inflammation, all inhibited by exogenous melatonin. Thus, we demonstrated that cytosolic mtDNA activated the inflammatory response in aging and neurodegeneration, a process modulated by melatonin. Furthermore, our data suggest that AANAT knockout mice are a model of accelerated aging.
Abhishek Jauhari, Sergei V. Baranov, Yalikun Suofu, Jinho Kim, Tanisha Singh, Svitlana Yablonska, Fang Li, Xiaomin Wang, Patrick Oberly, M. Beth Minnigh, Samuel M. Poloyac, Diane L. Carlisle, Robert M. Friedlander
Original citation: J Clin Invest. 2020;130(6):3124–3136. https://doi.org/10.1172/JCI135026
Citation for this corrigendum: J Clin Invest. 2021;131(9):e150328. https://doi.org/10.1172/JCI150328
We identified errors in seven figure panels in this manuscript: Figures 1F, 2C, 2E, 3C, and 7E and Supplemental Figures 1E and 7A. These errors were identified as the result of a thorough review of each figure panel after discrepancies were noted by a reader after publication. When the concern was brought to our attention, we reviewed all the data for every panel in the publication. In the data review, we reexamined the original raw data for each figure. We informed the JCI of the errors in these panels and provided the raw data to the editors for their review. This information was also provided for an independent institutional evaluation. The correct data are consistent with the conclusions made in the original article. In this Corrigendum, the seven incorrect figure panels are replaced with the correct panels made from the original raw data. In addition, anti-caspase 1 antibody (catalog 22915-1-AP, Proteintech), which was omitted from the reagent list in Supplemental Table 2, has been added to the updated supplemental file.
We regret the errors.
In Figure 1F the band labeled “cleaved caspase-1 (p45)” should have been labeled “cleaved caspase-1 (p10).” The correctly labeled image is below.
In Figure 2C, the β-actin Western blot image was inadvertently duplicated. The correct corresponding β-actin images are shown below with their respective Western blots.
In Figure 2E, the IL-18 data were inadvertently replaced with a duplicate of the IL-1β data. The correct panel for IL-18 is shown below.
In Figure 3C, the IRF3 data were inadvertently replaced with a duplicate of the cGAS data. The correct IRF3 panel is shown below.
In Figure 7E, the IRF3 panel was inadvertently replaced with a duplicate of the STING panel. The correct panel for IRF3 densitometric quantification is shown below.
In Supplemental Figure 1E, 20-week IL-6 data were inadvertently replaced with a duplicate of the IL-1β data. The 8-week data were correct. The correct panel for IL-6 is shown below.
In Supplemental Figure 7A, the panel on the far right was inadvertently mislabeled as IRF3 rather than STING. The correct panel is shown below.