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MKK3 deletion improves mitochondrial quality.

Publication ,  Journal Article
Srivastava, A; McGinniss, J; Wong, Y; Shinn, AS; Lam, TT; Lee, PJ; Mannam, P
Published in: Free radical biology & medicine
October 2015

Sepsis, a severe response to infection, leads to excessive inflammation and is the major cause of mortality in intensive care units. Mitochondria have been shown to influence the outcome of septic injury. We have previously shown that MAP kinase kinase 3 (MKK3)(-/-) mice are resistant to septic injury and MKK3(-/-) macrophages have improved mitochondrial function. In this study we examined processes that lead to improved mitochondrial quality in MKK3(-/-) mouse embryonic fibroblasts (MEFs) and specifically the role of mitophagy in mitochondrial health. MKK3(-/-) MEFs had lower inflammatory cytokine release and oxidant production after lipopolysaccharide (LPS) stimulation, confirming our earlier observations. MKK3(-/-) MEFs had better mitochondrial function as measured by mitochondrial membrane potential (MMP) and ATP, even after LPS treatment. We observed higher mitophagy in MKK3(-/-) MEFs compared to wild type (WT). Transmission electron microscopy studies showed longer and larger mitochondria in MKK3(-/-) MEFs, indicative of healthier mitochondria. We performed a SILAC (stable isotope labeling by/with amino acids in cell culture) study to assess differences in mitochondrial proteome between WT and MKK3(-/-) MEFs and observed increased expression of tricarboxylic acid (TCA) cycle enzymes and respiratory complex subunits. Further, inhibition of mitophagy by Mdivi1 led to loss in MMP and increased cytokine secretion after LPS treatment in MKK3(-/-) MEFs. In conclusion, this study demonstrates that MKK3 influences mitochondrial quality by affecting the expression of mitochondrial proteins, including TCA cycle enzymes, and mitophagy, which consequently regulates the inflammatory response. Based on our results, MKK3 could be a potential therapeutic target for inflammatory diseases like sepsis.

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Published In

Free radical biology & medicine

DOI

EISSN

1873-4596

ISSN

0891-5849

Publication Date

October 2015

Volume

87

Start / End Page

373 / 384

Related Subject Headings

  • Sepsis
  • Mitophagy
  • Mitochondria
  • Microscopy, Electron, Transmission
  • Mice, Knockout
  • Mice
  • Macrophages
  • MAP Kinase Kinase 3
  • Isotope Labeling
  • Inflammation
 

Citation

APA
Chicago
ICMJE
MLA
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Srivastava, A., McGinniss, J., Wong, Y., Shinn, A. S., Lam, T. T., Lee, P. J., & Mannam, P. (2015). MKK3 deletion improves mitochondrial quality. Free Radical Biology & Medicine, 87, 373–384. https://doi.org/10.1016/j.freeradbiomed.2015.06.024
Srivastava, Anup, John McGinniss, Yao Wong, Amanda S. Shinn, TuKiet T. Lam, Patty J. Lee, and Praveen Mannam. “MKK3 deletion improves mitochondrial quality.Free Radical Biology & Medicine 87 (October 2015): 373–84. https://doi.org/10.1016/j.freeradbiomed.2015.06.024.
Srivastava A, McGinniss J, Wong Y, Shinn AS, Lam TT, Lee PJ, et al. MKK3 deletion improves mitochondrial quality. Free radical biology & medicine. 2015 Oct;87:373–84.
Srivastava, Anup, et al. “MKK3 deletion improves mitochondrial quality.Free Radical Biology & Medicine, vol. 87, Oct. 2015, pp. 373–84. Epmc, doi:10.1016/j.freeradbiomed.2015.06.024.
Srivastava A, McGinniss J, Wong Y, Shinn AS, Lam TT, Lee PJ, Mannam P. MKK3 deletion improves mitochondrial quality. Free radical biology & medicine. 2015 Oct;87:373–384.
Journal cover image

Published In

Free radical biology & medicine

DOI

EISSN

1873-4596

ISSN

0891-5849

Publication Date

October 2015

Volume

87

Start / End Page

373 / 384

Related Subject Headings

  • Sepsis
  • Mitophagy
  • Mitochondria
  • Microscopy, Electron, Transmission
  • Mice, Knockout
  • Mice
  • Macrophages
  • MAP Kinase Kinase 3
  • Isotope Labeling
  • Inflammation