Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

Minton, Denise R.; Nam, Minwoo; McLaughlin, Daniel J.; Shin, Jong; Bayraktar, Erol C.; Alvarez, Samantha; Sviderskiy, Vladislav O.; Papagiannakopoulos, Thales; Sabatini, David M.; Birsoy, Kıvanç; Possemato, Richard

doi:10.1016/j.molcel.2018.01.024

Cited by 147 publications

(170 citation statements)

References 43 publications

Supporting

Mentioning

147

Contrasting

Order By: Relevance

“…It is therefore possible that this response limits that ability of the cell to combat oxidative stress that occurs during mitochondrial dysfunction. It is also important to consider the contribution of serine catabolism to mitochondrial translation, as serine contributes to the formylation of Met-tRNAfMet and perturbations in this pathway result in OXPHOS defects (Minton et al, 2018). This is apparent in our AGKKO proteomics data ( Table 1) where there is a striking defect in the levels of numerous mtDNA encoded subunits, including MT-ATP6, MT-ND1, and MT-ND4.…”

Section: Discussionmentioning

confidence: 96%

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

Jackson

Hock

Palmer

et al. 2020

Preprint

View full text Add to dashboard Cite

words)The Acylglycerol Kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations inAGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. We undertook proteomic profiling of Sengers patient fibroblasts and an AGKKO cell line to map the proteomic changes that ensue upon AGK dysfunction. This uncovered extensive remodelling of mitochondrial one-carbon metabolism enzymes and showed that inner membrane serine transporters, Sideroflexins (SFXNs), are novel substrates of the TIM22 complex. Deletion of SFXN1 recapitulates the remodelling of onecarbon metabolism observed in Sengers patient cells. Proliferation of cells lacking AGK is perturbed in the absence of exogenous serine and rescuable through addition of formate, highlighting the dysregulation of one carbon metabolism as a key molecular feature in the biology of Sengers syndrome.

show abstract

Section: Discussionmentioning

confidence: 96%

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

Jackson

Hock

Palmer

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…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%

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

Long

Zhou

et al. 2020

FASEB j.

View full text Add to dashboard Cite

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.

show abstract

“…Blocking folate recycling effectively ablates folate-dependent processes that require rapid turnovers in the respective compartment. Hence, deletion of SHMT2 , MTHFD2 , or MTHFD1L in cell lines results in a similar glycine-requiring growth phenotype (Ducker et al, 2016), although mitochondrial protein translation, for which the demand for 1C is quantitatively small, is affected differentially (Minton et al, 2018; Morscher et al, 2018). …”

Section: Introductionmentioning

confidence: 99%

Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells

Zheng

Lin

Lee

et al. 2018

Cell

View full text Add to dashboard Cite

SUMMARY Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

show abstract

Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs

Cited by 147 publications

References 43 publications

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

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

Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells

Contact Info

Product

Resources

About