Physiological and pathological roles of mitochondrial SLC25 carriers

Gutiérrez‐Aguilar, Manuel; Baines, Christopher P.

doi:10.1042/bj20121753

Cited by 110 publications

(89 citation statements)

References 221 publications

(286 reference statements)

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“…Citrate is generated in the mitochondria, but it is an important substrate for biosynthesis in the cytosol upstream of IDH1 (23). As a mitochondrial citrate carrier (CIC), SLC25A1 promotes the efflux of citrate from mitochondria into the cytosol (24)(25)(26), where it can be converted into oxaloacetate and acetyl-CoA by ATP citrate lyase (ACL) or into isocitrate by aconitase 1 (Aco1) and then oxidized by IDH1 to generate NADPH and α-KG. Both acetyl-CoA and NADPH are the substrates for lipid biosynthesis, which is critical for cell proliferation, and therefore, SLC25A1 is an important molecule upstream of IDH1.…”

Section: Discussionmentioning

confidence: 99%

IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to α-ketoglutarate (α-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wildtype (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular α-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing α-KG-dependent transamination of glucogenic AAs such as alanine.isocitrate dehydrogenase 1 | α-ketoglutarate | gluconeogenesis | transamination | liver I socitrate dehydrogenases (IDH) convert isocitrate to α-ketoglutarate (α-KG) by reducing NADP + or NAD + . The recent discovery of IDH1 and IDH2 mutations in human cancers (1-4) has elicited new interest in defining IDH1's functions in vivo, which are still poorly understood. IDH1 is abundant in liver and was reported to participate in lipid biosynthesis in hepatocyte cytoplasm and peroxisomes (5, 6). Mutant mice overexpressing IDH1 in liver and adipose tissue are obese, have fatty livers, and show elevated plasma triglycerides (TG) and cholesterol (7). In tumor cells, IDH1 contributes to de novo lipogenesis by generating acetyl-CoA building blocks via the NADPH-dependent reductive carboxylation of α-KG to isocitrate (8-11). However, IDH1-null mice at steady-state are healthy and fertile, maintain normal body weight, and show no inflammatory symptoms (12).The liver maintains normal blood glucose levels through glycogenolysis and gluconeogenesis. Gluconeogenesis generates glucose from noncarbohydrate carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids (AAs). During prolonged fasting, the breakdown of skeletal muscle generates limited carbon resources in the form of AAs such as alanine. Hence, both fasting and feeding of a high-protein diet (HPD) can stimulate AA deamination and urea production in the liver (13), where AA carbon skeletons are converted into glucose or lipids. For most AAs, the amino group is transferred to α-KG to generate glutama...

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Section: Discussionmentioning

confidence: 99%

IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The high homology existing between SLC25A33 and SLC25A36 has suggested that these two members of the MCF might have similar functions (1,2). However, the substrate(s) transported by SLC25A36 has not yet been discovered, and its function is still completely elusive.…”

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confidence: 99%

“…The human genome harbors as many as 53 SLC25 genes encoding a superfamily of transport proteins called solute carrier 25 (SLC25) 3 family or mitochondrial carrier family (MCF) (1,2). The members of this family are characterized by three tandem repeated sequences of ϳ100 amino acids, each folded into two transmembrane ␣-helices and containing a distinct signature motif (PROSITE PS50920, PFAM PF00153, and IPR00193).…”

mentioning

confidence: 99%

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

Noia

Todisco

Cirigliano

et al. 2014

Journal of Biological Chemistry

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Background: SLC25A33 and SLC25A36 are two human uncharacterized proteins encoded by the mitochondrial carrier SLC25 genes. Results: Recombinant SLC25A33 and SLC25A36 transport cytosine, uracil, and thymine (deoxy)nucleotides with different efficiency. Conclusion: SLC25A33 and SLC25A36 are mitochondrial transporters for pyrimidine (deoxy)nucleotides. Significance: SLC25A33 and SLC25A36 are essential for mitochondrial DNA and RNA metabolism; other two members of the SLC25 superfamily responsible for 12 monogenic diseases were thoroughly characterized.

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“…The mitochondrial carrier system ( MCS ) (“see glossary”) transports small molecules between mitochondria and the cytoplasm, thereby regulating the function of both compartments [1–3]. In mammals, the MCS comprises the transporters of the 53 member canonical SLC25A family and a lesser number of identified non-canonical transporters.…”

Section: The Mitochondrial Carrier Systemmentioning

confidence: 99%

“…This is significant because understanding the systems-level function of the MCS may provide new opportunities for therapeutic metabolic reprogramming. For detailed coverage of the history of mitochondrial carrier research, the reader is referred to several excellent review articles [1–3, 24, 25]. …”

Section: The Mitochondrial Carrier Systemmentioning

confidence: 99%

Functional Properties of the Mitochondrial Carrier System

Taylor

2017

Trends in Cell Biology

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The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53 member canonical SLC25A family and a lesser number of identified non-canonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular-genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.

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Physiological and pathological roles of mitochondrial SLC25 carriers

Cited by 110 publications

References 221 publications

IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

Functional Properties of the Mitochondrial Carrier System

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