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

One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in human cells for genes of the mitochondrial pathway, we found sideroflexin 1 (SFXN1), a multipass inner mitochondrial membrane protein of unclear function. Like cells missing mitochondrial components of one-carbon metabolism, those null for SFXN1 are defective in glycine and purine synthesis. Cells lacking SFXN1 and one of its four homologs, SFXN3, have more severe defects, including being auxotrophic for glycine. Purified SFXN1 transports serine in vitro. Thus, SFXN1 functions as a mitochondrial serine transporter in one-carbon metabolism.

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Bax Is Present as a High Molecular Weight Oligomer/Complex in the Mitochondrial Membrane of Apoptotic Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m010810200 ◽

2001 ◽

Vol 276 (15) ◽

pp. 11615-11623 ◽

Cited By ~ 486

Author(s):

Bruno Antonsson ◽

Sylvie Montessuit ◽

Belen Sanchez ◽

Jean-Claude Martinou

Keyword(s):

Molecular Weight ◽

Membrane Protein ◽

Hela Cells ◽

Mitochondrial Membrane ◽

Outer Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

Voltage Dependent Anion Channel ◽

Large Molecular Weight ◽

Mitochondrial Membrane Protein

Bax is a Bcl-2 family protein with proapoptotic activity, which has been shown to trigger cytochromecrelease from mitochondria bothin vitroandin vivo. In control HeLa cells, Bax is present in the cytosol and weakly associated with mitochondria as a monomer with an apparent molecular mass of 20,000 Da. After treatment of the HeLa cells with the apoptosis inducer staurosporine or UV irradiation, Bax associated with mitochondria is present as two large molecular weight oligomers/complexes of 96,000 and 260,000 Da, which are integrated into the mitochondrial membrane. Bcl-2 prevents Bax oligomerization and insertion into the mitochondrial membrane. The outer mitochondrial membrane protein voltage-dependent anion channel and the inner mitochondrial membrane protein adenosine nucleotide translocator do not coelute with the large molecular weight Bax oligomers/complexes on gel filtration. Bax oligomerization appears to be required for its proapoptotic activity, and the Bax oligomer/complex might constitute the structural entirety of the cytochromec-conducting channel in the outer mitochondrial membrane.

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The TIM22 complex mediates the import of Sideroflexins and is required for efficient mitochondrial one-carbon metabolism

Molecular Biology of the Cell ◽

10.1091/mbc.e20-06-0390 ◽

2021 ◽

pp. mbc.E20-06-0390

Author(s):

Thomas D. Jackson ◽

Daniella H. Hock ◽

Kenji M. Fujihara ◽

Catherine S. Palmer ◽

Ann E. Frazier ◽

...

Keyword(s):

Carbon Metabolism ◽

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

Molecular Feature ◽

Lipid Kinase ◽

Skeletal Myopathy ◽

A Subunit ◽

Sengers Syndrome ◽

Mitochondrial Lipid ◽

One Carbon Metabolism

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 in AGK cause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. We mapped the proteomic changes in Sengers patient fibroblasts and AGKKO cell lines to understand the effects of AGK dysfunction on mitochondria. This uncovered downregulation of a number of proteins at the inner mitochondrial membrane, including many SLC25 carrier family proteins, which are predicted substrates of the complex. We also observed downregulation of SFXN proteins, which contain five transmembrane domains, and show that they represent a novel class of TIM22 complex substrate. Perturbed biogenesis of SFXN proteins in cells lacking AGK reduces the proliferative capabilities of these cells in the absence of exogenous serine, suggesting that dysregulation of one carbon metabolism is a molecular feature in the biology of Sengers syndrome.

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Faculty Opinions recommendation of MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12481.469965 ◽

2006 ◽

Author(s):

Michio Hirano

Keyword(s):

Mitochondrial Dna ◽

Membrane Protein ◽

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Dna Depletion ◽

Mitochondrial Membrane Protein

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Bc1-2 as an inner mitochondrial membrane protein that blocks programmed cell death D. Hockenbery et al. Nature 348, 334–336

Trends in Genetics ◽

10.1016/0168-9525(91)90031-k ◽

1991 ◽

Vol 7 (1) ◽

pp. 43

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Membrane Protein ◽

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Membrane Protein

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Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study

Nutrients ◽

10.3390/nu12020580 ◽

2020 ◽

Vol 12 (2) ◽

pp. 580

Author(s):

Camilo G. Sotomayor ◽

Isidor Minović ◽

Manfred L. Eggersdorfer ◽

Ineke J. Riphagen ◽

Martin H. de Borst ◽

...

Keyword(s):

Vitamin E ◽

Carbon Metabolism ◽

Serum Vitamin ◽

Elderly Subjects ◽

Vitamin Supplement ◽

Total Lipids ◽

Metabolism Pathway ◽

Age Related ◽

One Carbon Metabolism ◽

The One

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

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High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease

Science Advances ◽

10.1126/sciadv.aax9484 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaax9484 ◽

Cited By ~ 30

Author(s):

Kristian Parey ◽

Outi Haapanen ◽

Vivek Sharma ◽

Harald Köfeler ◽

Thomas Züllig ◽

...

Keyword(s):

Complex I ◽

Mitochondrial Membrane ◽

Electrochemical Gradient ◽

Inner Mitochondrial Membrane ◽

Respiratory Complex ◽

Access Path ◽

Respiratory Complex I ◽

Assembly Intermediate ◽

The One ◽

Complex I Assembly

Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I–linked disease and complex I assembly in the inner mitochondrial membrane.

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Maternal vitamin D deficiency impact on LCPUFA and pregnancy outcome associated with alterations in the one carbon metabolism

Nutrition Research ◽

10.1016/j.nutres.2020.11.009 ◽

2020 ◽

Author(s):

Anindita A. Nandi ◽

Nisha S. Wadhwani ◽

Karuna N. Randhir ◽

Shweta D. Madiwale ◽

Juilee S. Deshpande ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Pregnancy Outcome ◽

Carbon Metabolism ◽

Maternal Vitamin ◽

One Carbon Metabolism ◽

The One

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Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

Oncology ◽

10.1159/000509658 ◽

2020 ◽

Vol 98 (12) ◽

pp. 897-904

Author(s):

Sook Kyung Do ◽

Sun Ha Choi ◽

Shin Yup Lee ◽

Jin Eun Choi ◽

Hyo-Gyoung Kang ◽

...

Keyword(s):

Lung Cancer ◽

Carbon Metabolism ◽

Genetic Variants ◽

Early Stage ◽

Small Cell ◽

Survival Outcomes ◽

Small Cell Lung ◽

Metabolism Pathway ◽

One Carbon Metabolism ◽

The One

Background: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). Methods: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. Results: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, p = 0.03, respectively). Conclusions: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

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In Vitro Import of a Nuclearly Encoded tRNA into the Mitochondrion of Trypanosoma brucei

Molecular and Cellular Biology ◽

10.1128/mcb.19.9.6253 ◽

1999 ◽

Vol 19 (9) ◽

pp. 6253-6259 ◽

Cited By ~ 33

Author(s):

Audra E. Yermovsky-Kammerer ◽

Stephen L. Hajduk

Keyword(s):

Membrane Potential ◽

Trypanosoma Brucei ◽

Mitochondrial Membrane ◽

Protein Component ◽

Proper Function ◽

Mitochondrial Rna ◽

Inner Mitochondrial Membrane ◽

Trna Import ◽

Trna Substrate

ABSTRACT All of the mitochondrial tRNAs of Trypanosoma bruceihave been shown to be encoded in the nucleus and must be imported into the mitochondrion. The import of nuclearly encoded tRNAs into the mitochondrion has been demonstrated in a variety of organisms and is essential for proper function in the mitochondrion. An in vitro import assay has been developed to study the pathway of tRNA import inT. brucei. The in vitro system utilizes crude isolated trypanosome mitochondria and synthetic RNAs transcribed from a cloned nucleus-encoded tRNA gene cluster. The substrate, composed of tRNASer and tRNALeu, is transcribed in tandem with a 59-nucleotide intergenic region. The tandem tRNA substrate is imported rapidly, while the mature-size tRNALeu fails to be imported in this system. These results suggest that the preferred substrate for tRNA import into trypanosome mitochondria is a precursor molecule composed of tandemly linked tRNAs. Import of the tandem tRNA substrate requires (i) a protein component that is associated with the surface of the mitochondrion, (ii) ATP pools both outside and within the mitochondrion, and (iii) a membrane potential. Dissipation of the proton gradient across the inner mitochondrial membrane by treatment with an uncoupling agent inhibits import of the tandem tRNA substrate. Characterization of the import requirements indicates that mitochondrial RNA import proceeds by a pathway including a protein component associated with the outer mitochondrial membrane, ATP-dependent steps, and a mitochondrial membrane potential.

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