The acetylation of MDH1 and IDH1 is associated with energy metabolism in acute liver failure

Shi, Chunxia; Zhang, Yanqiong; Chen, Qian; Wang, Yukun; Zhang, Danmei; Guo, Jin; Zhang, Qingqi; Zhang, Wenbin; Gong, Zuojiong

doi:10.1016/j.isci.2024.109678

Cited by 2 publications

(2 citation statements)

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“…In our previous studies, we found that the acetylation of MDH1 K118 and IDH1 K93 is closely related to the activity and function of MDH1 and IDH1 [ 15 , 16 ]. Therefore, in this study, we mutated the MDH1 K118 and IDH1 K93 sites (lysine K mutated to arginine R) to simulate deacetylation.…”

Section: Resultsmentioning

confidence: 99%

“…Studies have reported that the acetylation of MDH1 and IDH1 can affect their activities and function in diseases [ 22 , 23 ]. In our previous studies, we found that the deacetylation of MDH1 K118 and IDH1 K93 reduced the activity and function of MDH1 and IDH1, respectively [ 15 , 16 ]. The dysfunction of MDH1 and IDH1 can disrupt energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

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

Shi,

Wang,

Guo

et al. 2024

Cell Death Discov.

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Acute liver failure (ALF) is a disease with a high mortality rate and poor prognosis, whose pathogenesis is not fully understood. PANoptosis is a recently proposed mode of cell death characterized by pyroptosis, apoptosis, and necroptosis, but it cannot be explained by any of them alone. This study aims to explore the role of PANoptosis in ALF and the impact and mechanism of deacetylated malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) on PANoptosis. Our results found that, compared with the control group, the cell viability in the lipopolysaccharide (LPS)/D-galactosamine (D-Gal) group decreased, lactate dehydrogenase (LDH) release increased, cell death increased, and the levels of PANoptosis-related molecules RIPK1, GSDMD, caspase-3, MLKL, IL-18, IL-1β increased, indicating that PANoptosis increased during ALF. Deacetylated MDH1 at K118 and IDH1 at K93 increased the expression of PANoptosis-related molecules RIPK1, GSDMD, caspase-3, MLKL, IL-18, and IL-1β in vivo and in vitro. The deacetylation weakened the inhibitory effect of histone deacetylase (HDAC) inhibitor ACY1215 on PANoptosis-related molecules, suggesting that deacetylated MDH1 at K118 and IDH1 at K93 aggravated PANoptosis during ALF. Deacetylated MDH1 at K118 and IDH1 at K93 also promoted the expression of endoplasmic reticulum stress-related molecules BIP, ATF6, XBP1, and CHOP in vivo and in vitro. The use of endoplasmic reticulum stress inhibitor 4-PBA weakened the promotion effect of deacetylated MDH1 K118 and IDH1 K93 on PANoptosis. The results suggested that deacetylated MDH1 at K118 and IDH1 at K93 may aggravate PANoptosis in ALF through endoplasmic reticulum stress signaling. In conclusion, deacetylated MDH1 and IDH1 may aggravate PANoptosis in ALF, and the mechanism may act through endoplasmic reticulum stress signaling.

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Section: Resultsmentioning

confidence: 99%