Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate

Zhao, Mingguo; Yao, Pengbo; Mao, Youxiang; Wu, Jinjun; Wang, Weihua; Geng, Chenhui; Cheng, Jie; Du, Wenjing; Jiang, Peng

doi:10.1038/s42255-022-00532-w

Cited by 24 publications

(20 citation statements)

References 47 publications

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“…First, ME2 may regulate differentiation by regulating chromatin modification through 2‐hydroxyglutarate (2‐HG). ME2 can promote 2‐HG production to inhibit the activity of dioxygenases, 50,51 such as ten‐eleven translocation (TET) enzymes and histone demethylases (JHDMs), 21 ultimately affecting the histone and DNA methylations that dictate stem cell differentiation. We previously showed that MT suppresses DNA methylation during odontogenic differentiation; it can therefore be deduced that MT regulates DNA methylation via ME2 17 .…”

Section: Discussionmentioning

confidence: 99%

Melatonin‐mediated malic enzyme 2 orchestrates mitochondrial fusion and respiratory functions to promote odontoblastic differentiation during tooth development

Zhang

Yang

Jiang

et al. 2023

Journal of Pineal Research

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Tooth development is a complex process that is tightly controlled by circadian rhythm. Melatonin (MT) is a major hormonal regulator of the circadian rhythm, and influences dentin formation and odontoblastic differentiation during tooth development; however, the underlying mechanism remains elusive. This study investigated how MT regulates odontoblastic differentiation, with a special focus on its regulation of mitochondrial dynamics. In rat dental papilla cells (DPCs), we found that MT promotes odontoblastic differentiation concurrently with enhanced mitochondrial fusion, while disruption of mitochondrial fusion by depleting optic atrophy 1 (OPA1) impairs MT‐mediated differentiation and mitochondrial respiratory functions. Through RNA sequencing, we discovered that MT significantly upregulated malic enzyme 2 (ME2), a mitochondrial NAD(P)+‐dependent enzyme, and identified ME2 as a critical MT downstream effector that orchestrates odontoblastic differentiation, mitochondrial fusion, and respiration functions. By detecting the spatiotemporal expression of ME2 in developing tooth germs, and using tooth germ reconstituted organoids, we also provided in vivo and ex vivo evidence that ME2 promotes dentin formation, indicating a possible involvement of ME2 in MT‐modulated tooth development. Collectively, our findings offer novel understandings regarding the molecular mechanism by which MT affects cell differentiation and organogenesis, meanwhile, the critical role of ME2 in MT‐regulated mitochondrial functions is also highlighted.

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Section: Discussionmentioning

confidence: 99%

Melatonin‐mediated malic enzyme 2 orchestrates mitochondrial fusion and respiratory functions to promote odontoblastic differentiation during tooth development

Zhang

Yang

Jiang

et al. 2023

Journal of Pineal Research

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“…RNA extraction and quantitative PCR analysis were carried out as described previously (Zhao et al , 2022). RNA was extracted by TRIzol according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

p53 protects against alcoholic fatty liver disease via ALDH2 inhibition

et al. 2023

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The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol‐induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl‐CoA and histone acetylation, leading to the inhibition of the stearoyl‐CoA desaturase‐1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53‐deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver‐specific knockdown of SCD1 alleviates ethanol‐induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol‐induced fatty liver development in wild‐type mice, while it has a mild effect on p53−/− or ALDH2−/− mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol‐induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.

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“…the major ME isoform in mitochondria, ME2 has the highest abundance and enzymatic activity in this organelle and participates in the tricarboxylic acid cycle and glutamine metabolism. In line with this, by adjusting glutaminolysis, ME2 can modulate the 2-HG production from glutamine ( Zhao et al, 2022 ). 2-HG is an oncometabolite generated by reducing the ketone group of α-ketoglutarate to a hydroxyl group.…”

mentioning

confidence: 88%

“…In a recent publication ( Zhao et al, 2022 ), we reported a novel function of ME2 in regulating the protein stability of mutp53 by the oncometabolite 2-hydroxyglutarate (2-HG) ( Figure 1B ). In cancer cells, ME2 promotes the generation of 2-HG not only by adjusting glutaminolysis but also through a catalytic reaction that requires pyruvate and reduced NADP (NADPH).…”

mentioning

confidence: 96%

Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate

Cited by 24 publications

References 47 publications

Melatonin‐mediated malic enzyme 2 orchestrates mitochondrial fusion and respiratory functions to promote odontoblastic differentiation during tooth development

Melatonin‐mediated malic enzyme 2 orchestrates mitochondrial fusion and respiratory functions to promote odontoblastic differentiation during tooth development

p53 protects against alcoholic fatty liver disease via ALDH2 inhibition

Malic enzyme 2 as a therapeutic target for cancer: comments on ‘Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate’

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