Abstract
Mitochondrial DNA (mtDNA) has many similarities with bacterial DNA because of their shared common ancestry. Increasing evidence demonstrates mtDNA to be a potent danger signal that is recognised by the innate immune system and can directly modulate the inflammatory response. In humans, elevated circulating mtDNA is found in conditions with significant tissue injury such as trauma and sepsis and increasingly in chronic organ-specific and systemic illnesses such as steatohepatitis and systemic lupus erythematosus. In this review, we examine our current understanding of mtDNA-mediated inflammation and how the mechanisms regulating mitochondrial homeostasis and mtDNA release represent exciting and previously under-recognised important factors in many human inflammatory diseases, offering many new translational opportunities.
Highlights
Mitochondria are intracellular double-membrane-bound organelles (“cellular powerhouses”) with many essential physiological roles in energy production, programmed cell death, calcium homeostasis, and the synthesis of lipids, amino acids, and haem
Mitochondria are evolutionarily derived from energy-producing alpha-bacteria, engulfed by archezoan cells approximately 2 billion years ago leading to a symbiotic relationship that forms the basis of the eukaryotic cells[3]
No significant difference in mitochondrial DNA (mtDNA) between non-survivors and survivors in severe sepsis mtDNA higher on admission in severe septic patients than in HCs mtDNA is higher in non-survivors than in survivors, increases initially and gradually decreases after antimicrobial therapy, and is an independent predictor of fatality mtDNA higher in septic patients compared with HCs mtDNA higher in patients with septic shock mtDNA levels were higher in patients with aseptic or bacterial meningitis compared with HCs mtDNA levels fall during course of admission
Summary
Mitochondria are intracellular double-membrane-bound organelles (“cellular powerhouses”) with many essential physiological roles in energy production, programmed cell death, calcium homeostasis, and the synthesis of lipids, amino acids, and haem. Uncontrolled release of mtDNA into the circulation in conditions with significant tissue injury generates a more systemic effect whilst de-regulation of local mitochondrial homeostatic mechanisms such as autophagy or mtROS detoxification contributes to organspecific pathology as observed in the heart and liver Failure of such mechanisms may give rise to a more wide-ranging consequence (for example, in autoimmune diseases such as SLE). There are many plausible approaches, which include targeting cytosolic mtDNA release (for example, directly at MPT using cyclosporine or by specific mitochondrial anti-oxidant strategies, such as MitoQ1010 to reduce mtROS), augmenting clearance (for example, using autophagy activators or correcting factors leading to impaired autophagy), diverting the cellular response following mitochondrial damage (for example, induction of pro-apoptotic caspases), and reducing the inflammatory potential of mtDNA (for example, DNases to digest NET-bound mtDNA and reducing oxidation of mtDNA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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