Desai Radha, East Daniel A, Hardy Liana, Faccenda Danilo, Rigon Manuel, Crosby James, Alvarez María Soledad, Singh Aarti, Mainenti Marta, Hussey Laura Kuhlman, Bentham Robert, Szabadkai Gyorgy, Zappulli Valentina, Dhoot Gurtej K, Romano Lisa E, Xia Dong, Coppens Isabelle, Hamacher-Brady Anne, Chapple J Paul, Abeti Rosella, Fleck Roland A, Vizcay-Barrena Gema, Smith Kenneth, Campanella Michelangelo
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.
Department of Cell and Developmental Biology, Consortium for Mitochondrial Research (CfMR), University College London, Gower Street, London WC1E 6BT, UK.
Sci Adv. 2020 Dec 18;6(51). doi: 10.1126/sciadv.abc9955. Print 2020 Dec.
Mitochondria drive cellular adaptation to stress by retro-communicating with the nucleus. This process is known as mitochondrial retrograde response (MRR) and is induced by mitochondrial dysfunction. MRR results in the nuclear stabilization of prosurvival transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Here, we demonstrate that MRR is facilitated by contact sites between mitochondria and the nucleus. The translocator protein (TSPO) by preventing the mitophagy-mediated segregation o mitochonria is required for this interaction. The complex formed by TSPO with the protein kinase A (PKA), via the A-kinase anchoring protein acyl-CoA binding domain containing 3 (ACBD3), established the tethering. The latter allows for cholesterol redistribution of cholesterol in the nucleus to sustain the prosurvival response by blocking NF-κB deacetylation. This work proposes a previously unidentified paradigm in MRR: the formation of contact sites between mitochondria and nucleus to aid communication.
线粒体通过与细胞核进行逆向通讯来驱动细胞对压力的适应性。这一过程被称为线粒体逆向反应（MRR），由线粒体功能障碍所诱导。MRR导致促生存转录因子（如活化B细胞核因子κB轻链增强子，NF-κB）在细胞核中稳定。在此，我们证明线粒体与细胞核之间的接触位点促进了MRR。转运蛋白（TSPO）通过防止线粒体自噬介导的线粒体分离，是这种相互作用所必需的。TSPO与蛋白激酶A（PKA）通过含3的A激酶锚定蛋白酰基辅酶A结合结构域（ACBD3）形成的复合物建立了连接。后者使细胞核中的胆固醇重新分布，通过阻止NF-κB去乙酰化来维持促生存反应。这项工作提出了MRR中一个以前未被识别的范例：线粒体与细胞核之间形成接触位点以辅助通讯。
