Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells

Lucas, Stéphanie; Chen, Guohua; Aras, Siddhesh; Wang, Jian

doi:10.26508/lsa.201800036

Cited by 60 publications

(70 citation statements)

References 46 publications

(74 reference statements)

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“…Previous studies have emphasized that serine availability is critical for the maintenance of cellular anti‐oxidative capacity and mitochondrial function in cancer cells . Recently, studies further suggested that de novo serine synthesis and serine catabolism also play important roles in maintaining cellular redox balance and mitochondrial respiration in normal mammalian cells . These studies mostly focused on the role of serine in metabolism such as support of de novo ATP synthesis and provision of the one‐carbon unit.…”

Section: Discussionmentioning

confidence: 99%

“…4,10 Recently, studies further suggested that de novo serine synthesis and serine catabolism also play important roles in maintaining cellular redox balance and mitochondrial respiration in normal mammalian cells. 3,12 These studies mostly focused on the role of serine in metabolism such as support of de novo ATP synthesis and provision of the one-carbon unit. In our study, we found that serine deficiency exacerbated oxidative stress and cellular apoptosis in IPEC-J2 cells under oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Rapidly proliferating cells can both utilize serine exogenously and serine from the de novo synthesis pathway . Recently, serine availability has been suggested to influence mitochondrial function and cellular respiration in proliferating cells . However, no studies have focused on the role of exogenous serine on cell proliferation and apoptosis in the intestine that are under oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Long

Zhou

et al. 2020

FASEB j.

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Serine has critical roles in maintaining cell growth and redox balance in cancer cells. However, the role of exogenous serine played in oxidative response and proliferation in normal mammalian intestine need to be further elucidated. We used a mouse model and intestinal porcine epithelial cells (IPEC‐J2) to reveal that exogenous serine deficiency did not lead to redox imbalance and inhibition of proliferation in the intestine. However, serine deficiency exacerbated oxidative stress, mitochondrial dysfunction, apoptosis, and inhibition of proliferation in IPEC‐J2 cells challenged by hydrogen peroxide, while serine supplementation rescued redox imbalance and those proliferation defects. Importantly, serine supplementation restored the glutathione content and decreased the accumulation of reactive oxygen species, while no such effects were observed when glutathione synthesis was inhibited. Additionally, serine supplementation increased nuclear nrf2 expression in IPEC‐J2 cells. These results suggested that serine alleviates oxidative stress through supporting glutathione synthesis and activating nrf2 signaling. We further found that serine supplementation activated the mTOR pathway, while inhibition of mTOR diminished the effects of serine on promoting proliferation, suggesting critical roles of the mTOR pathway in this context. Taken together, our study underlines the importance of serine in the maintenance of redox status and proliferation in the intestine and reveals a novel potential mechanism that mediates these effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Long

Zhou

et al. 2020

FASEB j.

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“…In contrast to the above observations ( 73 , 77 ) that loss of SHMT2 leads to defective mitochondrial translation in cells, another study argued that the ability of an SHMT2-knockout 293A cell line to synthesize mitochondria-encoded proteins was not impaired when compared with the wild-type cells as determined using stable-isotope labeling ( 74 ). Instead, this study demonstrated that the regulation of the OXPHOS system by SHMT2 may take place after the translation of mtDNA-encoded proteins.…”

Section: Intracellular Compartmentalization Of One-carbon Metabolismmentioning

confidence: 95%

“…Recent studies have shown that mitochondrial FOCM enzymes are particularly strongly upregulated in proliferating lymphocytes and human cancers ( 17 , 69 – 71 ), which, in part, reflects the role of mitochondrial FOCM in supporting critical cellular functions such as cell proliferation and mitochondrial respiration. Some mitochondrial compartment–specific uses of mitochondrial folate one-carbon units include the local biosynthesis of dTTP ( 20 ) and of N -formylmethionine (fMet) ( 72 ), tRNA modification ( 73 ), oxidative phosphorylation (OXPHOS) complex assembly ( 74 ) and redox state regulation ( 75 , 76 ).…”

Section: Intracellular Compartmentalization Of One-carbon Metabolismmentioning

confidence: 99%

The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function

Xiu

Field

2020

Current Developments in Nutrition

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Folate-mediated one-carbon metabolism (FOCM) is compartmentalized within human cells to the cytosol, nucleus, and mitochondria. The recent identifications of mitochondria-specific, folate-dependent thymidylate (dTMP) synthesis together with discoveries indicating the critical role of mitochondrial FOCM in cancer progression has renewed interest in understanding this metabolic pathway. The goal of this narrative review is to summarize recent advances in the field of one-carbon metabolism, with an emphasis on the biological importance of mitochondrial FOCM in maintaining mitochondrial DNA (mtDNA) integrity and mitochondrial function, as well as the reprogramming of mitochondrial FOCM in cancer. Elucidation of the roles and regulation of mitochondrial FOCM will contribute to a better understanding of the mechanisms underlying folate-associated pathologies.

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ASC‐1 transporter‐dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation

et al. 2021

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Brown and beige adipocytes dissipate energy by uncoupling protein 1 (UCP1)-dependent andindependent thermogenesis, which may be utilized to develop treatments against obesity. We have found that mRNA and protein expression of the alanine-serine-cysteine transporter-1 (ASC-1) was induced during adipocyte differentiation of human brown-prone deep neck and beigecompetent subcutaneous neck progenitors, and SGBS preadipocytes. cAMP stimulation of differentiated adipocytes led to elevated uptake of serine, cysteine, and glycine, in parallel with increased oxygen consumption, augmented UCP1-dependent proton leak, increased creatine-driven substrate cycle coupled respiration, and upregulation of thermogenesis marker genes and several respiratory complex subunits; these outcomes were impeded in the presence of the specific ASC-1 inhibitor, BMS-466442. Our data suggest that ASC-1-dependent consumption of serine, cysteine, and glycine is required for efficient thermogenic stimulation of human adipocytes.

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Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells

Abstract: Mitochondrial respiratory complex assembly requires the one-carbon unit generated from serine catabolism.

Cited by 60 publications

References 46 publications

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

Serine is required for the maintenance of redox balance and proliferation in the intestine under oxidative stress

The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function

ASC‐1 transporter‐dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation

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