Mitochondrial DNA in innate immune responses and inflammatory pathology

West, A. Phillip; Shadel, Gerald S.

doi:10.1038/nri.2017.21

Cited by 783 publications

(761 citation statements)

References 124 publications

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“…High-level exposures may result in increased fission, which blocks efficient ATP generation and limits rates of functional complementation, in addition to potentially leading to apoptosis. Highly fragmented mitochondria may be more likely to undergo cellular export (West and Shadel 2017), potentially eliciting an inflammatory response, as discussed by West (this issue). Mitochondrial fission may also inhibit the response to infection (Khan et al 2015).…”

Section: Mitochondrial Fusion and Fission As Stress Responsesmentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.

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Section: Mitochondrial Fusion and Fission As Stress Responsesmentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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“…Although they signal through different pathways, they both induce a pronounced type 1 IFN response, which primarily functions to suppress virus infection, but when overexaggerated may by itself induce cell damage in the brain (Rice et al 2012;Baruch et al 2014). Interestingly, this pathway can also be activated by liberation of RNA or DNA into the cytoplasm of damaged cells and in particular by intra-and extracellular release of mitochondrial DNA (West and Shadel 2017).…”

Section: Cytotoxicity-oxidative Activationmentioning

confidence: 99%

Microglial Phenotypes and Functions in Multiple Sclerosis

O’Loughlin

Madore

Lassmann

et al. 2018

Cold Spring Harb Perspect Med

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“…While carrying out oxidative phosphorylation, mitochondria also facilitate decomposition of reactive oxygen species (ROS), calcium homeostasis, thermoregulation and cell death amongst other functions [12, 13]. Our mitochondrial genome is uniquely and exclusively of maternal origin [14].…”

Section: Mitochondria and Mtdnamentioning

confidence: 99%

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

Thurairajah

Briggs

Balogh

2018

Eur J Trauma Emerg Surg

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Mitochondria play a key role in the pathophysiology of post-injury inflammation. Cell-free mitochondrial DNA (cf-mtDNA) is now understood to catalyse sterile inflammation after trauma. Observations in trauma cohorts have identified high cf-mtDNA in patients with systemic inflammatory response syndrome and multiple organ failure as well as following major surgery. The source of cf-mtDNA can be various cells affected by mechanical and hypoxic injury (passive mechanism) or induced by inflammatory mechanisms (active mechanism). Multiple forms of cf-mtDNA exist; mtDNA fragments, mtDNA in microparticles/vesicles and cell-free mitochondria. Trauma to cells that are rich in mitochondria are believed to release more cf-mtDNA. This review describes the current understanding of the mechanisms of cf-mtDNA release, its systemic effects and the potential therapeutic implications related to its modification. Although current understanding is insufficient to change trauma management, focussed research goals have been identified to pave the way for monitoring and manipulation of cf-mtDNA release and effects in trauma.

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Mitochondrial DNA in innate immune responses and inflammatory pathology

Cited by 783 publications

References 124 publications

Mitochondrial fusion, fission, and mitochondrial toxicity

Mitochondrial fusion, fission, and mitochondrial toxicity

Microglial Phenotypes and Functions in Multiple Sclerosis

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

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