Mitochondrial MTHFD2L Is a Dual Redox Cofactor-specific Methylenetetrahydrofolate Dehydrogenase/Methenyltetrahydrofolate Cyclohydrolase Expressed in Both Adult and Embryonic Tissues

Shin, Minsoo; Bryant, Joshua D.; Momb, Jessica; Appling, Dean R.

doi:10.1074/jbc.m114.555573

Cited by 44 publications

(65 citation statements)

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“…Thus, formate released by mitochondria can feed cytosolic 1C pools and thereby nucleotide synthesis and methylation. An important difference between the cytosolic and mitochondrial 1C pathways is cofactor usage for the dehydrogenase step: cytosolic MTHFD1 uses NADP(H) while mitochondrial MTHFD2 primarily uses NAD(H) (Shin et al, 2014). This likely results in more rapid oxidative dehydrogenase flux to formyl-THF in the mitochondrion.…”

Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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Decades ago Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events, which drive aberrant cancer cell proliferation, also alter biochemical metabolism including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy, provide building blocks for new cells, and control redox homeostasis, oncogenic signaling, innate immunity and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mitochondrial DNA limits tumorigenesis and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multi-functional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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Section: Mitochondria Integrate Catabolism Anabolism and Signalingmentioning

confidence: 99%

Mitochondria and Cancer

2016

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“…Hypersuccinylated SHMT2 proteins purified from HEK293T cells were incubated with purified SIRT3, SIRT5, or SIRT5- SHMT2-specific enzymatic activity assay SHMT2 activity assay contains two continuous reactions: SHMT2 catalyzes THF and serine to 5, 10-CH 2 -THF, and then MTHFD2 catalyzes the 5,10-CH 2 -THF to 10-CH 2 -THF accompanied with NAD(P)H production, which can be measured (37). Different states of SHMT2 proteins and same quantity GST-MTHFD2 proteins were subjected into activity assay buffer, and increase in absorbance at 350 nm was measured every minute for 30 minutes at 37 C. THF, serine, NAD …”

Section: In Vitro Desuccinylation Assaymentioning

confidence: 99%

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

et al. 2018

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The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372-86.Ó2017 AACR.

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“…Recent studies have suggested that the benefit to cancer cells of high MTHFD2 expression may be independent of the metabolic functions of the enzyme. An alternative enzyme, MTHFD2L, has been identified to also be able to catalyse the oxidation of CH 2 -THF and is expressed in adult cells 14,15 . Another recent study has also found that MTHFD2 localized to the nucleus and that over-expression of the enzyme was sufficient to promote proliferation independent of its dehydrogenase activity 16 …”

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confidence: 99%