Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Tigano, Marco; Vargas, Danielle C.; Tremblay‐Belzile, Samuel; Fu, Yi; Sfeir, Agnel

doi:10.1038/s41586-021-03269-w

Cited by 222 publications

(179 citation statements)

References 49 publications

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…3E) possibly caused by ActD intercalation within the mitochondrial genome. Such mtDNA release, followed by activation of cGAS, and its downstream IFN pathway could activate senescence, as well as anti-leukemic immune responses (31,36,47,48). Besides cGAS activation, ActD induces ROS which are required for ActD-induced senescence ex vivo through PML NB reformation and TP53 activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Rérolle

Berthier

et al. 2021

Cancer Discovery

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of PML nuclear bodies (NBs), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mtDNA, activating cGAS signaling and boosting ROS production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCEActinomycin D induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML bodies (NBs).Actinomycin D targets mitochondria, yielding ROS which enforce PML NB-biogenesis and restore senescence. Dual targeting of mitochondria with actinomycin D and venetoclax sharply potentiates their anti-AML activities in vivo.Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Rérolle

Berthier

et al. 2021

Cancer Discovery

View full text Add to dashboard Cite

show abstract

“…5 ). Other DAMPs are mitochondrial double-stranded RNA (dsRNA), including RNA released in response to mtDNA double-strand breaks ( Tigano et al, 2021 ), metabolites such as ATP, N-formyl peptides and even TFAM (see Box 2 ) ( Rodriguez-Nuevo and Zorzano, 2019 ). Also, TFAM deficiency, via defective mtDNA packaging, causes mtDNA to escape into the cytosol ( West et al, 2015 ).…”

Section: Mtdna As Driver Of the Innate Immune Responsementioning

confidence: 99%

Mitochondrial function in development and disease

Rossmann

Dubois

Agarwal

et al. 2021

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

Mitochondria are organelles with vital functions in almost all eukaryotic cells. Often described as the cellular ‘powerhouses’ due to their essential role in aerobic oxidative phosphorylation, mitochondria perform many other essential functions beyond energy production. As signaling organelles, mitochondria communicate with the nucleus and other organelles to help maintain cellular homeostasis, allow cellular adaptation to diverse stresses, and help steer cell fate decisions during development. Mitochondria have taken center stage in the research of normal and pathological processes, including normal tissue homeostasis and metabolism, neurodegeneration, immunity and infectious diseases. The central role that mitochondria assume within cells is evidenced by the broad impact of mitochondrial diseases, caused by defects in either mitochondrial or nuclear genes encoding for mitochondrial proteins, on different organ systems. In this Review, we will provide the reader with a foundation of the mitochondrial ‘hardware’, the mitochondrion itself, with its specific dynamics, quality control mechanisms and cross-organelle communication, including its roles as a driver of an innate immune response, all with a focus on development, disease and aging. We will further discuss how mitochondrial DNA is inherited, how its mutation affects cell and organismal fitness, and current therapeutic approaches for mitochondrial diseases in both model organisms and humans.

show abstract

“…These broken DNA fragments can leak into the cytosol, where they are recognized by the PPRs. Sensors such as cGAS, IFI16 and RIG-I but also STING have been linked to genomic instability [ 129 , 130 , 131 , 132 , 133 ]. This crosstalk between genomic instability, DNA repair and innate immunity is critical in maintaining cell homeostasis, and currently there is an increased interest in the use of immune nucleic acid sensing pathways in targeting cancer [ 134 ].…”

Section: Damps Connect Dna Damage and Innate Immunity During Hpv Infectionmentioning

confidence: 99%

Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection

Gusho

Laimins

2021

Viruses

View full text Add to dashboard Cite

Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.

show abstract

Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Cited by 222 publications

References 49 publications

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Mitochondrial function in development and disease

Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection

Contact Info

Product

Resources

About