Mitochondrial SLC25 Carriers: Novel Targets for Cancer Therapy

The transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy.

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The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+

Biochemical Journal ◽

10.1042/bj20111420 ◽

2012 ◽

Vol 443 (1) ◽

pp. 241-247 ◽

Cited By ~ 79

Author(s):

Gennaro Agrimi ◽

Annamaria Russo ◽

Pasquale Scarcia ◽

Ferdinando Palmieri

Keyword(s):

Human Gene ◽

Main Function ◽

Human Tissues ◽

Solute Carrier Family ◽

Peroxisomal Membrane ◽

Mitochondrial Carrier ◽

Mitochondrial Carrier Family ◽

Solute Carrier ◽

Identification And Characterization

The essential cofactors CoA, FAD and NAD+ are synthesized outside the peroxisomes and therefore must be transported into the peroxisomal matrix where they are required for important processes. In the present study we have functionally identified and characterized SLC25A17 (solute carrier family 25 member 17), which is the only member of the mitochondrial carrier family that has previously been shown to be localized in the peroxisomal membrane. Recombinant and purified SLC25A17 was reconstituted into liposomes. Its transport properties and kinetic parameters demonstrate that SLC25A17 is a transporter of CoA, FAD, FMN and AMP, and to a lesser extent of NAD+, PAP (adenosine 3′,5′-diphosphate) and ADP. SLC25A17 functioned almost exclusively by a counter-exchange mechanism, was saturable and was inhibited by pyridoxal 5′-phosphate and other mitochondrial carrier inhibitors. It was expressed to various degrees in all of the human tissues examined. Its main function is probably to transport free CoA, FAD and NAD+ into peroxisomes in exchange for intraperoxisomally generated PAP, FMN and AMP. The present paper is the first report describing the identification and characterization of a transporter for multiple free cofactors in peroxisomes.

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The mitochondrial carrier pathway transports non-canonical substrates with an odd number of transmembrane segments

BMC Biology ◽

10.1186/s12915-019-0733-6 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 10

Author(s):

Heike Rampelt ◽

Iva Sucec ◽

Beate Bersch ◽

Patrick Horten ◽

Inge Perschil ◽

...

Keyword(s):

Intermembrane Space ◽

Inner Mitochondrial Membrane ◽

Inner Membrane ◽

Mitochondrial Carrier ◽

Transmembrane Segments ◽

Mitochondrial Inner Membrane ◽

N Terminus ◽

The Matrix ◽

Mitochondrial Carrier Family ◽

Mitochondrial Intermembrane Space

Abstract Background The mitochondrial pyruvate carrier (MPC) plays a central role in energy metabolism by transporting pyruvate across the inner mitochondrial membrane. Its heterodimeric composition and homology to SWEET and semiSWEET transporters set the MPC apart from the canonical mitochondrial carrier family (named MCF or SLC25). The import of the canonical carriers is mediated by the carrier translocase of the inner membrane (TIM22) pathway and is dependent on their structure, which features an even number of transmembrane segments and both termini in the intermembrane space. The import pathway of MPC proteins has not been elucidated. The odd number of transmembrane segments and positioning of the N-terminus in the matrix argues against an import via the TIM22 carrier pathway but favors an import via the flexible presequence pathway. Results Here, we systematically analyzed the import pathways of Mpc2 and Mpc3 and report that, contrary to an expected import via the flexible presequence pathway, yeast MPC proteins with an odd number of transmembrane segments and matrix-exposed N-terminus are imported by the carrier pathway, using the receptor Tom70, small TIM chaperones, and the TIM22 complex. The TIM9·10 complex chaperones MPC proteins through the mitochondrial intermembrane space using conserved hydrophobic motifs that are also required for the interaction with canonical carrier proteins. Conclusions The carrier pathway can import paired and non-paired transmembrane helices and translocate N-termini to either side of the mitochondrial inner membrane, revealing an unexpected versatility of the mitochondrial import pathway for non-cleavable inner membrane proteins.

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A New Renal Mitochondrial Carrier, KMCP1, Is Up-regulated during Tubular Cell Regeneration and Induction of Antioxidant Enzymes

Journal of Biological Chemistry ◽

10.1074/jbc.m412136200 ◽

2005 ◽

Vol 280 (23) ◽

pp. 22036-22043 ◽

Cited By ~ 22

Author(s):

Anne Haguenauer ◽

Serge Raimbault ◽

Sandrine Masscheleyn ◽

Maria del Mar Gonzalez-Barroso ◽

Francois Criscuolo ◽

...

Keyword(s):

Redox Balance ◽

Mitochondrial Metabolism ◽

Antioxidant Defenses ◽

Kidney Cortex ◽

Inner Mitochondrial Membrane ◽

Mitochondrial Carrier ◽

Mitochondrial Carrier Family ◽

Distal Tubules ◽

Oxidant Status

The mitochondrial carrier family transports a variety of metabolites across the inner mitochondrial membrane. We identified and cloned a new member of this family, KMCP1 (kidney mitochondrial carrier protein-1), that is highly homologous to the previously identified protein BMCP1 (brain mitochondrial carrier protein-1). Western blotting and in situ experiments showed that this carrier is expressed predominantly within the kidney cortex in the proximal and distal tubules. KMCP1 was increased during fasting and during the regenerative phase of glycerol-induced renal failure. We show that both situations are associated with transiently increased expression of superoxide-generating enzymes, followed by increased mitochondrial metabolism and antioxidant defenses. Given that KMCP1 expression occurs simultaneously with these latter events, we propose that KMCP1 is involved in situations in which mitochondrial metabolism is increased, in particular when the cellular redox balance tends toward a pro-oxidant status.

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Proteomic and Bioinformatic Profiling of Transporters in Higher Plant Mitochondria

Biomolecules ◽

10.3390/biom10081190 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1190 ◽

Cited By ~ 1

Author(s):

Ian Max Møller ◽

R. Shyama Prasad Rao ◽

Yuexu Jiang ◽

Jay J. Thelen ◽

Dong Xu

Keyword(s):

Plant Mitochondria ◽

Inorganic Ions ◽

Proteomic Profiling ◽

Inner Mitochondrial Membrane ◽

Higher Plant ◽

Inner Membrane ◽

Mitochondrial Carrier ◽

Protein Uptake ◽

Mitochondrial Carrier Family ◽

Unexplored Area

To function as a metabolic hub, plant mitochondria have to exchange a wide variety of metabolic intermediates as well as inorganic ions with the cytosol. As identified by proteomic profiling or as predicted by MU-LOC, a newly developed bioinformatics tool, Arabidopsis thaliana mitochondria contain 128 or 143 different transporters, respectively. The largest group is the mitochondrial carrier family, which consists of symporters and antiporters catalyzing secondary active transport of organic acids, amino acids, and nucleotides across the inner mitochondrial membrane. An impressive 97% (58 out of 60) of all the known mitochondrial carrier family members in Arabidopsis have been experimentally identified in isolated mitochondria. In addition to many other secondary transporters, Arabidopsis mitochondria contain the ATP synthase transporters, the mitochondria protein translocase complexes (responsible for protein uptake across the outer and inner membrane), ATP-binding cassette (ABC) transporters, and a number of transporters and channels responsible for allowing water and inorganic ions to move across the inner membrane driven by their transmembrane electrochemical gradient. A few mitochondrial transporters are tissue-specific, development-specific, or stress-response specific, but this is a relatively unexplored area in proteomics that merits much more attention.

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