BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis

Lun Cai, Ali S. Arbab, Tae Jin Lee, Ashok Sharma, Bobby Thomas, Kazuhiko Igarashi, Raghavan Pillai Raju

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Sepsis is a complex disease due to dysregulated host response to infection. Oxidative stress and mitochondrial dysfunction leading to metabolic dysregulation are among the hallmarks of sepsis. The transcription factor NRF2 (Nuclear Factor E2-related factor2) is a master regulator of the oxidative stress response, and the NRF2 mediated antioxidant response is negatively regulated by BTB and CNC homology 1 (BACH1) protein. This study tested whether Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP). We observed enhanced post-CLP survival in Bach1−/− mice with a concomitantly increased liver HO-1 expression, reduced liver injury and oxidative stress, and attenuated systemic and tissue inflammation. After sepsis induction, the liver mitochondrial function was better preserved in Bach1−/− mice. Furthermore, BACH1 deficiency improved liver and lung blood flow in septic mice, as measured by SPECT/CT. RNA-seq analysis identified 44 genes significantly altered in Bach1−/− mice after sepsis, including HMOX1 and several genes in lipid metabolism. Inhibiting HO-1 activity by Zinc Protoporphyrin-9 worsened organ function in Bach1−/− mice following sepsis. We demonstrate that mitochondrial bioenergetics, organ function, and survival following experimental sepsis were improved in Bach1−/− mice through the HO-1-dependent mechanism and conclude that BACH1 is a therapeutic target in sepsis.

Original languageEnglish (US)
Pages (from-to)134-145
Number of pages12
JournalFree Radical Biology and Medicine
Volume188
DOIs
StatePublished - Aug 1 2022

Keywords

  • Antioxidant
  • BACH1
  • Cellular energetics
  • Mitochondria
  • NRF2
  • Oxidative stress
  • Sepsis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis'. Together they form a unique fingerprint.

Cite this