AbstractMitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization..

摘要线粒体功能障碍可引起多种炎症途径，特别是当凋亡的半胱天冬酶被抑制时。这种炎症程序受到通透性线粒体自噬处理的负面调节。最近的数据表明，线粒体蛋白的泛素化对于NEMO驱动的线粒体通透性下游NF-kB活化至关重要。。

Mitochondrial outer membrane permeabilization (MOMP) is a key regulator of intrinsic apoptosis. MOMP occurs upon the oligomerization of BCL2 associated X, apoptosis regulator (BAX) and BCL2 antagonist/killer 1 (BAK1) on the outer mitochondrial membrane (OMM), a process that is inhibited by BCL2 apoptosis regulator (BCL2), BCL2 like 1 (BCL2L1, best known as BCL-XL) and MCL1 apoptosis regulator, BCL2 family member (MCL1) [1].

线粒体外膜通透性（MOMP）是内在细胞凋亡的关键调节因子。MOMP发生在线粒体外膜（OMM）上BCL2相关X，凋亡调节剂（BAX）和BCL2拮抗剂/杀伤剂1（BAK1）的寡聚化后，这一过程被BCL2凋亡调节剂（BCL2），BCL2样1（BCL2L1，最着名的BCL-XL）和MCL1凋亡调节剂BCL2家族成员（MCL1）抑制。

Besides precipitating apoptotic cell death, MOMP promotes the cytosolic accumulation of multiple pro-inflammatory molecules, including (but not limited to) mitochondrial DNA and RNA species, as well as cardiolipin [2, 3]. Importantly, several systems are in place to prevent MOMP from eliciting unwarranted inflammatory reactions in physiological scenarios.

。重要的是，有几种系统可以防止MOMP在生理情况下引起不必要的炎症反应。

On the one hand, cells adapting to sublethal stress conditions, in which MOMP involves a limited fraction of the mitochondrial network (so-called “minority MOMP”) [4], can rapidly degrade permeabilized mitochondria (and hence limit the availability of pro-inflammatory molecules) through an ubiquitin-dependent specialized variant of autophagy commonly known as mitophagy [5, 6].

一方面，适应亚致死应激条件的细胞，其中MOMP涉及线粒体网络的有限部分（所谓的“少数MOMP”）〔4〕，可以快速降解透化的线粒体（从而限制促炎分子的可用性），通过泛素依赖的自噬特异性变体，通常称为线粒体自噬[5，6]。

On the other hand, cells succumbing to MOMP during physiological waves of apoptosis, for instance as underlying the renewal of epithelial layers, massively activate post-mitochondrial caspases, notably caspase 3 (CASP3), which has multipronged anti-inflammatory effects [3, 7].One of the central mechanism through which MOMP elicits inflammation (in the context of caspase inhibition) involves the activation of an NF-κB-dependent transcriptional program elicited by inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB, best known as IKKβ) and inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG, bes.

另一方面，细胞在凋亡的生理波中屈服于MOMP，例如作为上皮层更新的基础，大量激活线粒体后半胱天冬酶，特别是半胱天冬酶3（CASP3），其具有多重抗炎作用[3，7]。MOMP引发炎症（在半胱天冬酶抑制的情况下）的中心机制之一涉及激活由核因子κB激酶亚基β（IKBKB，最着名为IKKβ）抑制剂和核因子κB激酶调节亚基γ（IKBKG，bes）抑制剂引发的NF-κB依赖性转录程序。

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Download referencesAcknowledgementsThe LG lab is/has been supported (as a PI unless otherwise indicated) by one NIH R01 grant (#CA271915), by two Breakthrough Level 2 grants from the US DoD BCRP (#BC180476P1, #BC210945), by a grant from the STARR Cancer Consortium (#I16-0064), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (#W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (#CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by a pre-SPORE grant (PI: Demaria, Formenti), a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center (New York, US), by startup funds from the Dept.

下载参考文献致谢LG实验室得到了一项NIH R01拨款（#CA271915），美国国防部BCRP的两项突破性2级拨款（#BC180476P1，#BC210945），STARR癌症协会的拨款（#I16-0064），美国国防部BCRP的转化性乳腺癌协会拨款（#W81XWH2120034，PI:Formenti），NIH/NCI的U54拨款（#CA274; 291，PI:Deasy，Formenti，Weichselbaum），2019年Laura Ziskin转化研究奖（ZP-6177，PI:Formenti），来自癌症（SU2C），来自白血病和淋巴瘤协会（LLS）的套细胞淋巴瘤研究计划（MCL-RI，PI:Chen Kiang），来自功能基因组学计划（美国纽约）的快速反应资助，孢子前资助（PI:Demaria，Formenti），来自桑德拉和爱德华·迈耶癌症中心（美国纽约）的合作研究计划资助和临床试验创新资助来自部门。

of Radiation Oncology at Weill Cornell Medicine (New York, US), by industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, US) and Onxeo (Paris, France), as well as by donations from Promontory (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia).Author informationAuthors and AffiliationsDepartment of Radiation Oncology, Weill Cornell Medicine, New York, NY, USAEmma Guilbaud & Lorenzo GalluzziSandra and Edward Meyer Cancer Center, New York, NY, USALorenzo GalluzziCaryl and Israel Englander Institute for Precision Medicine, New York, NY, USALorenzo GalluzziAuthorsEmma Guilbaud.

通过与Lytix Biopharma（挪威奥斯陆），Promentory（美国纽约）和Onxeo（法国巴黎）的工业合作，以及来自Promentory（美国纽约），Luke Heller TECPR2基金会（美国波士顿），Sotio a.s.（捷克共和国布拉格），Lytix Biopharma（挪威奥斯陆），Onxeo（法国巴黎），Ricerchiamo（意大利布雷西亚）和Noxopharm（澳大利亚查茨伍德）的捐赠，在威尔康奈尔医学（美国纽约）进行放射肿瘤学研究。。

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PubMed Google ScholarContributionsLG conceived the article. EG and LG wrote the first version of the manuscript. EG generated display items under supervision from LG. Both authors approve the submitted version of the article.Corresponding authorCorrespondence to

。EG和LG写了手稿的第一版。EG在LG的监督下生成显示项目。两位作者都批准了文章的提交版本。对应作者对应

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Competing interests

相互竞争的利益

LG is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options.

LG与Lytix Biopharma、Promentory和Onxeo签订了研究合同，获得了勃林格殷格翰、阿斯利康、OmniSEQ、Onxeo、长寿实验室、Inzen、Imvax、Sotio、Promentory、Noxopharm、EduCom和Luke Heller TECPR2基金会的咨询/顾问酬金，并持有Promentory股票期权。

EG has no conflicts of interest to declare..

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Cell Death Dis 15, 477 (2024). https://doi.org/10.1038/s41419-024-06868-3Download citationReceived: 21 May 2024Revised: 17 June 2024Accepted: 26 June 2024Published: 03 July 2024DOI: https://doi.org/10.1038/s41419-024-06868-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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