Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

Jin, Xiuxiu; Li, Li; Peng, Qinlu; Gan, Chunmei; Gao, Lei; He, Siyu; Tan, Shuangyan; Pu, Wenchen; Liu, Yu; Gong, Yanqiu; Yao, Yuqin; Wang, Gang; Liu, Xiaohui; Gong, Meng; Peng, Lei; Zhang, Huiyuan; Qi, Shiqian; Xu, Hong‐Xi; Hu, Hongbo; Dong, Biao; Peng, Yong; Su, Dan; Dai, Lunzhi

doi:10.1016/j.isci.2022.104349

Cited by 10 publications

(5 citation statements)

References 74 publications

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“…8A). Such decreased NAD/NADH indicates an accumulation of NADH, which has been observed more robustly in other immortalized cell models of homozygous Shmt2 loss and associated oxidative phosphorylation impairment [30,35].…”

Section: Discussionmentioning

confidence: 65%

Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity

et al. 2023

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Background Serine hydroxymethyltransferase 2 (SHMT2) catalyzes the reversible conversion of tetrahydrofolate (THF) and serine-producing THF-conjugated one-carbon units and glycine in the mitochondria. Biallelic SHMT2 variants were identified in humans and suggested to alter the protein’s active site, potentially disrupting enzymatic function. SHMT2 expression has also been shown to decrease with aging in human fibroblasts. Immortalized cell models of total SHMT2 loss or folate deficiency exhibit decreased oxidative capacity and impaired mitochondrial complex I assembly and protein levels, suggesting folate-mediated one-carbon metabolism (FOCM) and the oxidative phosphorylation system are functionally coordinated. This study examined the role of SHMT2 and folate availability in regulating mitochondrial function, energy metabolism, and cellular proliferative capacity in both heterozygous and homozygous cell models of reduced SHMT2 expression. In this study, primary mouse embryonic fibroblasts (MEF) were isolated from a C57Bl/6J dam crossed with a heterozygous Shmt2+/− male to generate Shmt2+/+ (wild-type) or Shmt2+/− (HET) MEF cells. In addition, haploid chronic myeloid leukemia cells (HAP1, wild-type) or HAP1 cells lacking SHMT2 expression (ΔSHMT2) were cultured for 4 doublings in either low-folate or folate-sufficient culture media. Cells were examined for proliferation, total folate levels, mtDNA content, protein levels of pyruvate kinase and PGC1α, pyruvate kinase enzyme activity, mitochondrial membrane potential, and mitochondrial function. Results Homozygous loss of SHMT2 in HAP1 cells impaired cellular folate accumulation and altered mitochondrial DNA content, formate production, membrane potential, and basal respiration. Formate rescued proliferation in HAP1, but not ΔSHMT2, cells cultured in low-folate medium. Pyruvate kinase activity and protein levels were impaired in ΔSHMT2 cells and in MEF cells exposed to low-folate medium. Mitochondrial biogenesis protein levels were elevated in Shmt2+/− MEF cells, while mitochondrial mass was increased in both homozygous and heterozygous models of SHMT2 loss. Conclusions The results from this study indicate disrupted mitochondrial FOCM impairs mitochondrial folate accumulation and respiration, mitochondrial formate production, glycolytic activity, and cellular proliferation. These changes persist even after a potentially compensatory increase in mitochondrial biogenesis as a result of decreased SHMT2 levels.

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Section: Discussionmentioning

confidence: 65%

Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity

et al. 2023

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“…[ 36 ] Further Western blotting experiments confirmed SHMT2 protein levels were significantly increased by KEN in a dose‐dependent manner (Figure 4G ), and SHMT2 knockdown abolished KEN‐induced enhancement of ADAM10 expression (Figure 4H ), indicating that SHMT2 mediated the effect of KEN on ADAM10 in vitro. It is reported that the small molecule Glycyrrhetinic acid (GA) directly binds to SHMT2 and suppresses mitochondrial energy metabolisms, [ 37 ] whereas another compound Cosmosiin enhances ADAM10 protein level via the 5′UTR‐dependent mechanism by our prior report. [ 16a ] To prove the effect of KEN on ADAM10 and the 5′UTR, we assessed ADAM10 and SHMT2 protein levels in SH‐SY5Y cells treated with KEN (0.75 µM for 36 h), in the absence or presence of SHMT2 inhibitor GA (100 µM) or Cosmosiin (Cos, 5 µM).…”

Section: Resultsmentioning

confidence: 93%

SHMT2 Mediates Small‐Molecule‐Induced Alleviation of Alzheimer Pathology Via the 5′UTR‐dependent ADAM10 Translation Initiation

Song,

Pan,

Zhou

et al. 2024

Advanced Science

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It is long been suggested that one‐carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small‐molecule kenpaullone (KEN) promoted ADAM10 translation via the 5′ untranslated region (5′UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5′UTR‐interacting RNA binding protein (RBP), mediated KEN‐induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5′UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5′UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 “moonlighted” as RBP by binding to GAGGG motif and promoting the 5′UTR‐dependent ADAM10 translation initiation.

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“…Multiple organelles might associate with ferroptotic cell death pathways, including endoplasmic reticulum stress which could be triggered by ferroptosis inducers through the Eif2α‐ATF4‐CHAC1 axis (Dixon et al, 2014; Lee, Lee, et al, 2019), Golgi stress (Alborzinia et al, 2018), and mitochondria. Mitochondria is particularly critical in ferroptotic cell death, playing a pivotal role in iron metabolism (Wang et al, 2020), and is associated with ROS metabolic process (Jin et al, 2022). Mitochondria damage has been shown in MCAO mouse models and OGD cell models, and is closely related to cerebral IRI (Zeng et al, 2022).…”

Section: The Role Of Iron In Ischemic Strokementioning

confidence: 99%

“…Mitochondria is particularly critical in ferroptotic cell death, playing a pivotal role in iron metabolism (Wang et al, 2020), and is associated with ROS metabolic process (Jin et al, 2022). Mitochondria damage has been shown in MCAO mouse models and OGD cell models, and is closely related to cerebral IRI (Zeng et al, 2022).…”

Section: Lipid Peroxidation and Ferroptosismentioning

confidence: 99%

Iron, ferroptosis, and ischemic stroke

Guo

Tuo

Lei

2023

Journal of Neurochemistry

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Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment of post-ischemic stroke remains a critical challenge.Recently, iron has emerged as a crucial factor in post-reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely, ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development.

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Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2

Cited by 10 publications

References 74 publications

Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity

Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity

SHMT2 Mediates Small‐Molecule‐Induced Alleviation of Alzheimer Pathology Via the 5′UTR‐dependent ADAM10 Translation Initiation

Iron, ferroptosis, and ischemic stroke

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