Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Lepelley, Alice; Mina, Erika Della; Nieuwenhove, Erika Van; Waumans, Lise; Fraïtag, Sylvie; Rice, Gillian I.; Dhir, Ashish; Frémond, Marie-Louise; Rodero, Mathieu P; Seabra, Luis; Carter, E.; Bodemer, Christine; Buhaş, Daniela; Callewaert, Bert; Lonlay, Pascale de; Somer, Lien De; Dyment, David A.; Faes, Fran; Grove, Lucy; Holden, Simon; Hully, Marie; Kurian, Manju A.; McMillan, Hugh J.; Suetens, Kristin; Tyynismaa, Henna; Chhun, Stéphanie; Wai, Timothy; Wouters, Carine; Bader‐Meunier, Brigitte; Crow, Yanick J.

doi:10.1101/2021.04.02.438201

Cited by 4 publications

(10 citation statements)

References 49 publications

(69 reference statements)

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“…Providing strong evidence of the potential of mtNA to induce pathological IFN induction in humans, inappropriate sensing of mtNA has recently been demonstrated in Mendelian diseases due to mutations in PNPT1 , NGLY1 and ATAD3A ( 73 , 76 , 77 ) ( Figure 2 ). These observations highlight mechanisms involved in mitochondrial homeostasis directly relevant to the avoidance of aberrant sensing of mtNA in human health.…”

Section: Immunostimulatory Mitochondrial Nucleic Acid In Type I Interferonopathiesmentioning

confidence: 99%

“…Very recently, we directly implicated, for the first time, mtDNA sensing in IFN induction in a Mendelian disease context ( 77 ). Specifically, we identified two patients demonstrating chronically enhanced IFN signaling in blood and features of systemic sclerosis, a rare autoimmune disorder where IFN signaling and mtDNA have been suggested to play a role in pathogenesis ( 81 – 83 ).…”

Section: Immunostimulatory Mitochondrial Nucleic Acid In Type I Interferonopathiesmentioning

confidence: 99%

“…While the contribution of defective oxidative phosphorylation and bioenergetic and metabolic stress is clear, the findings summarized above suggest that mtNA sensing driving IFN signaling may also be relevant to mitochondrial disease pathology. Thus, disease caused by mutations in PNPT1 and ATAD3A are considered as bona fide primary mitochondrial disorders, and might now also be included in the type I interferonopathy grouping ( 76 , 77 , 106 ). Mitochondrial disease is typically accompanied by various types of mitochondrial dysfunction and/or due to specific defects in mtNA metabolism ( 106 , 108 ), with the potential to cause mtNA release and sensing.…”

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

“…Thus, even if autoinflammation is not typically reported in mitochondrial disease ( 115 – 117 ), we suggest that increased IFN signaling may be more broadly associated with mitochondrial dysfunction than is currently appreciated, potentially contributing to the clinical phenotype beyond bioenergetic or metabolic defects. Indeed, enhanced interferon signaling related to ATAD3A dysfunction was only recognized six years after gene mutations were initially described ( 77 , 84 , 85 ). Further indication of a possible relationship between mitochondrial disease and the type I interferonopathies comes from shared clinical features, such as intracranial calcification being an established sign in both settings ( 3 , 118 ).…”

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

“…Similarly, bilateral striatal necrosis is recurrent in mitochondrial disease, and consistently described in the context of mutations in both PNPT1 ( 78 ) and the type I interferonopathy due to ADAR1 loss-of-function ( 119 ). Likewise, dystonia, peripheral neuropathy, hypertrophic cardiomyopathy and isolated spastic paraparesis, recorded in patients with mutations in ATAD3A ( 77 , 84 , 85 ), are features of interferon-related disease ( 120 , 121 ).…”

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

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Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

2021

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The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.

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Section: Immunostimulatory Mitochondrial Nucleic Acid In Type I Interferonopathiesmentioning

confidence: 99%

Section: Immunostimulatory Mitochondrial Nucleic Acid In Type I Interferonopathiesmentioning

confidence: 99%

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

Section: An Overlap Between Type I Interferonopathy and Mitochondrial Disease?mentioning

confidence: 99%

See 3 more Smart Citations

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

2021

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Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis

Zhou

Trinh-Minh

Tran-Manh

et al. 2022

Arthritis & Rheumatology

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Objective Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. Methods TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin‐induced skin fibrosis, bleomycin‐induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ). Results TFAM expression was down‐regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down‐regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long‐term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down‐regulation of TFAM and accumulation of mitochondrial damage. Down‐regulation of TFAM promoted fibroblast activation with up‐regulation of fibrosis‐relevant Gene Ontology terms in RNA‐Seq, partially in a reactive oxygen species–dependent manner. Mice with fibroblast‐specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Conclusion Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast‐to‐myofibroblast transition and drive tissue fibrosis.

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Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

et al. 2023

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Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

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Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Cited by 4 publications

References 49 publications

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis

Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

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