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Deacetylated MDH1 and IDH1 aggravates PANoptosis in acute liver failure through endoplasmic reticulum stress signaling

  • 0Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Death Discovery +

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June 8, 2024

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June 8, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Deacetylated malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) worsen acute liver failure (ALF) by increasing PANoptosis, a cell death process. This occurs through endoplasmic reticulum stress signaling, highlighting a potential therapeutic target for ALF.

Area Of Science

  • Cellular Biology
  • Pathology
  • Biochemistry

Background

  • Acute liver failure (ALF) is a severe condition with high mortality and poorly understood mechanisms.
  • PANoptosis, a complex cell death pathway involving pyroptosis, apoptosis, and necroptosis, has emerged as a significant area of research.

Purpose Of The Study

  • To investigate the role of PANoptosis in ALF.
  • To explore the impact and underlying mechanisms of deacetylated malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) on PANoptosis in ALF.

Main Methods

  • Induction of ALF using lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in vitro and in vivo.
  • Assessment of cell viability, lactate dehydrogenase (LDH) release, and levels of PANoptosis-related molecules (RIPK1, GSDMD, caspase-3, MLKL, IL-18, IL-1β).
  • Evaluation of endoplasmic reticulum (ER) stress markers (BIP, ATF6, XBP1, CHOP) and the effects of ER stress inhibitors (ACY1215, 4-PBA).

Main Results

  • ALF models exhibited increased PANoptosis, evidenced by decreased cell viability, increased LDH release, and elevated levels of PANoptosis markers.
  • Deacetylated MDH1 (at K118) and IDH1 (at K93) significantly increased PANoptosis-related molecules, counteracting the inhibitory effects of HDAC inhibitor ACY1215.
  • Deacetylated MDH1 and IDH1 promoted ER stress markers, and ER stress inhibition with 4-PBA attenuated their pro-PANoptosis effects.

Conclusions

  • Deacetylated MDH1 and IDH1 play a crucial role in exacerbating PANoptosis during ALF.
  • The mechanism involves the promotion of endoplasmic reticulum stress signaling pathways.
  • Targeting deacetylated MDH1, IDH1, or ER stress may offer novel therapeutic strategies for ALF.