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Regulation of mitochondrial biogenesis and its intersection with inflammatory responses
Anne D Cherry1, Claude A Piantadosi
11 Department of Anesthesiology, Duke University Medical Center , Durham, North Carolina.
Significance:
Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis.
Recent Advances:
Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression.
Critical Issues:
Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions.
Future Directions:
Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.
Insights
Mitochondria are crucial for cell health and can be damaged during inflammation. Cellular recovery relies on mitochondrial quality control, including biogenesis, which is influenced by inflammatory signals.
Area of Science:
- Cellular Biology
- Immunology
- Mitochondrial Medicine
Background:
- Inflammatory mediators activate pathways (NF-κB, MAPK, PKB/Akt) that regulate mitochondrial biogenesis via transcription factors like PGC-1α.
- Nitric oxide (NO), induced by inflammation, paradoxically causes mitochondrial dysfunction yet upregulates mitochondrial biogenesis and antioxidant responses.
- The inflammatory response, involving reactive oxygen species, activates the HO-1/CO system, promoting both mitochondrial biogenesis and antioxidant gene expression.
Purpose of the Study:
- To explore the intricate relationship between inflammation, mitochondrial dysfunction, and cellular recovery mechanisms.
- To elucidate the role of mitochondrial quality control programs, specifically mitochondrial biogenesis, in the context of inflammatory responses.
- To investigate the coupling of mitochondrial biogenesis and mitophagy through redox pathways during inflammation.
Main Methods:
- Analysis of inflammatory mediator protein interactions with pattern recognition receptors (PRRs).
- Investigation of signaling pathways including NF-κB, MAPK, and PKB/Akt.
- Examination of transcription factors regulating mitochondrial biogenesis (e.g., PGC-1α, NRF-1, NRF-2, Nfe2l2).
- Assessment of the role of nitric oxide (NO) and the HO-1/CO system in mitochondrial regulation.
- Exploration of redox pathway coupling between mitochondrial biogenesis and mitophagy, focusing on parkin.
Main Results:
- Evidence suggests mitochondrial biogenesis and mitophagy are coupled via redox pathways.
- Parkin, involved in mitophagy during chronic inflammation, may also influence mitochondrial biogenesis and is upregulated by NF-κB.
- Commonalities exist in host responses to acute and chronic inflammation, though direct extrapolation requires caution.
Conclusions:
- Inflammatory mitochondrial dysfunction and oxidative stress can perpetuate inflammation through DAMP/PRR interactions and inflammasome activation, stimulating mitophagy.
- Understanding how mitochondrial quality control impacts intracellular inflammatory signaling is key to restoring mitochondrial homeostasis during acute inflammation.
- Further research into parkin's role in acute inflammation is ongoing.
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