SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism

Kory, Nora; Wyant, Gregory A.; Prakash, Gyan; Bos, Jelmi uit de; Bottanelli, Francesca; Pacold, Michael E.; Chan, Sze Ham; Lewis, Caroline A.; Wang, Yichen; Keys, Heather R.; Guo, Yang; Sabatini, David M.

doi:10.1126/science.aat9528

Cited by 169 publications

(207 citation statements)

References 53 publications

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“…The pathway has cytosolic and mitochondrial branches, and a key step is the is the entry of serine into mitochondria. Transport of serine across the inner mitochondrial membrane was recently shown to be mediated by the SFXN protein family, in particular SFXN1 (Kory et al, 2018). In line with this, SFXN protein levels were reduced in both patient 1 and patient 2 fibroblasts and AGKKO HEK293 cells (Figure 1-C, right panels; Figure 1F-G).…”

Section: Mitochondrial 1c Metabolism Is Remodelled In Sengers Syndromesupporting

confidence: 72%

“…The proteomic approach employed in this study also uncovered extensive remodelling of key players involved in mitochondrial 1C metabolism in fibroblasts from patients with Sengers syndrome, including reduced levels of MTHFD2, MTHFD1L, SHMT2, ALDH1L2 and the SFXN proteins. SFXN proteins are inner mitochondrial membrane serine transporters that are required for mitochondrial 1C metabolism (Kory et al, 2018). Based on our analysis showing reduced import and assembly of SFXN proteins in mitochondria lacking AGK and Tim9, we suggest that that this family of proteins represent novel substrates of the TIM22 complex.…”

Section: Discussionmentioning

confidence: 74%

“…Together, this result suggests that depletion of SFXN levels due to TIM22 complex dysfunction may lead to further downstream remodelling of mitochondrial 1C metabolism. The mild effect observed in the SFXN1KO may be explained by the presence of SFXN2 and SFXN3, which can perform redundant functions in serine transport (Kory et al, 2018).…”

Section: Loss Of Agk Impairs Growth In the Absence Of Exogenous Serinementioning

confidence: 98%

“…In line with this, SFXN protein levels were reduced in both patient 1 and patient 2 fibroblasts and AGKKO HEK293 cells (Figure 1-C, right panels; Figure 1F-G). The SFXN family consists of five members (SFXN1-5), which are each predicted to contain five transmembrane domains embedded within the inner mitochondrial membrane (Kory et al, 2018). Based on this localisation and topology, we hypothesised that SFXNs represent a novel class of TIM22 complex substrates, and that their perturbed import in Sengers syndrome leads to dysregulation of 1C metabolism.…”

Section: Mitochondrial 1c Metabolism Is Remodelled In Sengers Syndromementioning

confidence: 99%

“…By analysing the proteomic data from patient cells alongside the proteomic footprint from an AGKKO HEK293 cell line, we identified sideroflexins (SFXNs), including the serine transporter SFXN1 (Kory et al, 2018), as novel substrates of the TIM22 complex. In vitro import analyses of SFXN proteins confirmed the requirement of the TIM22 complex for import, and we determined that loss of AGK in HEK293 cells led to dependency on exogenous serine for normal proliferation.…”

Section: Introductionmentioning

confidence: 99%

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

Jackson

Hock

Palmer

et al. 2020

Preprint

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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.

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Section: Mitochondrial 1c Metabolism Is Remodelled In Sengers Syndromesupporting

confidence: 72%

Section: Discussionmentioning

confidence: 74%

Section: Loss Of Agk Impairs Growth In the Absence Of Exogenous Serinementioning

confidence: 98%

Section: Mitochondrial 1c Metabolism Is Remodelled In Sengers Syndromementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Jackson

Hock

Palmer

et al. 2020

Preprint

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A homozygous missense variant in the WRN gene segregating in a family with progressive pulmonary failure with recurrent spontaneous pneumothorax and interstitial lung disease

Sezer

Kayhan

Gürsoy

et al. 2022

American J of Med Genetics Pt A

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Interstitial lung disease (ILD) is a condition affecting the lung parenchyma by inflammation and fibrosis and can be caused by various exposures, connective tissue diseases (CTD), and genetic disorders. In this report, a family with five patients having progressive respiratory failure that begins with coughing in adolescence, followed by dyspnea and recurrent spontaneous pneumothorax, and death in early adulthood is presented. The patients were diagnosed to have ILD through clinical and radiological evaluations. Molecular genetic analyses of the family provided two homozygous rare variants in the WRN and SFXN5 genes, co‐segregating with the phenotype. The network analyses pointed out that the variant in the WRN, rather than that in the SFXN5 gene, could be the main factor in the existence of the ILD phenotype, putatively through the altered DNA repair and telomere maintenance pathways. In silico analyses suggested that the variant could affect the exonuclease activity or the stability of the WRN protein. Moreover, the adolescent‐onset pulmonary phenotype described in the case has not been reported in Werner Syndrome, the only disease known to be associated with biallelic WRN pathogenic variants. Thus, the present phenotype could be either a very atypical presentation of Werner syndrome or a new clinical entity associated with the WRN gene.

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Generating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9

Giuliano

Lin

Girish

et al. 2019

CP Molecular Biology

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CRISPR/Cas9 technology enables the rapid generation of loss‐of‐function mutations in a targeted gene in mammalian cells. A single cell harboring those mutations can be used to establish a new cell line, thereby creating a CRISPR‐induced knockout clone. These clonal cell lines serve as crucial tools for exploring protein function, analyzing the consequences of gene loss, and investigating the specificity of biological reagents. However, the successful derivation of knockout clones can be technically challenging and may be complicated by multiple factors, including incomplete target ablation and interclonal heterogeneity. Here, we describe optimized protocols and plasmids for generating clonal knockouts in mammalian cell lines. We provide strategies for guide RNA design, CRISPR delivery, and knockout validation that facilitate the derivation of true knockout clones and are amenable to multiplexed gene targeting. These protocols will be broadly useful for researchers seeking to apply CRISPR to study gene function in mammalian cells. © 2019 The Authors.

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SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism

Cited by 169 publications

References 53 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

A homozygous missense variant in the WRN gene segregating in a family with progressive pulmonary failure with recurrent spontaneous pneumothorax and interstitial lung disease

Generating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9

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