Mitochondrial molecule controls inflammation

Article Multidisciplinary Sciences

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Alexander Hooftman et al.

Summary: Metabolic rewiring through an inflammatory aspartate-argininosuccinate shunt induces fumarate-mediated protein succination and inflammatory effects in macrophages. Inhibition of fumarate hydratase (FH) increases fumarate levels, suppresses mitochondrial respiration, and enhances interferon responses. FH inhibition may play a pathogenic role in systemic lupus erythematosus. These findings highlight the importance of FH in regulating macrophage functions and cytokine responses.

NATURE (2023)

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Article Multidisciplinary Sciences

Fumarate induces vesicular release of mtDNA to drive innate immunity

Vincent Zecchini et al.

Summary: The loss of FH in the kidney leads to early changes in mitochondrial morphology and the release of mtDNA into the cytosol, which activates the cGAS-STING-TBK1 pathway and induces an inflammatory response. This phenomenon is mediated by mitochondrial-derived vesicles and depends on SNX9. These findings demonstrate that increased levels of intracellular fumarate trigger a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, resulting in the release of mtDNA in the cytosol and the activation of the innate immune response.

NATURE (2023)

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Review Immunology

Mitochondrial control of inflammation

Saverio Marchi et al.

Summary: This article discusses the molecular mechanisms by which mitochondrial dysfunction leads to inflammatory reactions, the cellular pathways that regulate them, and the pathological consequences of dysregulated inflammatory responses elicited by mitochondrial damage-associated molecular patterns (DAMPs).

NATURE REVIEWS IMMUNOLOGY (2023)

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Article Cell Biology

Mitochondrial cristae architecture protects against mtDNA release and inflammation

Baiyu He et al.

Summary: This study reveals the crucial role of cristae architecture in preventing mtDNA release and inflammation. The disruption of cristae organizers leads to mtDNA release and the immune response. These findings provide mechanistic insights into the link between mitochondrial cristae disorganization and inflammation, which are emerging hallmarks of aging and age-related degenerative diseases.

CELL REPORTS (2022)

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Article Oncology

Genomic Characteristics and Single-Cell Profiles After Immunotherapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma

Pei Dong et al.

Summary: This study analyzed the genomic characteristics and microenvironment of FHRCC and the cause of heterogeneous response to immune checkpoint inhibitor (ICI)-based treatment. The results showed that FHRCC had frequent immune infiltration and ICI treatment was associated with improved overall response rate and disease control rate. However, ICI treatment could not reverse the exhaustion of CD8+ T cells in patients with progressive disease, highlighting the need for additional therapeutic strategies.

CLINICAL CANCER RESEARCH (2022)

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Article

Beyond ATP, new roles of mitochondria

Ram Prosad Chakrabarty et al.

Biochemist (2022)

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Article Multidisciplinary Sciences

Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Marco Tigano et al.

Summary: The study reveals that mtDSBs activate a type-I interferon response, leading to the phosphorylation of STAT1 and activation of interferon-stimulated genes. After breaks in mtDNA, herniation mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I-MAVS-dependent immune response.

NATURE (2021)

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Article Rheumatology

Circulating mitochondrial DNA copy numbers represent a sensitive marker for diagnosis and monitoring of disease activity in systemic lupus erythematosus

Stavros Giaglis et al.

Summary: The study found that circulating mtDNA levels are significantly increased in SLE patients compared to healthy controls, and are associated with SLE disease activity. mtDNA levels can sensitively distinguish SLE patients from healthy individuals and serve as an independent marker of SLE activity.

RMD OPEN (2021)

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Article Multidisciplinary Sciences

Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Kiran Todkar et al.

Summary: Mitochondrial content in extracellular vesicles (EVs) can exacerbate inflammation, while its role in non-inflammatory conditions remains unclear. The research demonstrates that mitochondria-derived vesicles target material to EVs, while Parkinson's disease-related protein Parkin directs damaged mitochondrial content to lysosomes, shedding light on mitochondria-driven immune responses.

NATURE COMMUNICATIONS (2021)

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Review Urology & Nephrology