SLC25A46 explained

Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria.^{[1] [2]} Mutations in this gene result in neuropathy and optic atrophy.^[3]

Structure

The SLC25A46 gene is located on the q arm of chromosome 5 in position 22.1 and spans 27,039 base pairs. The gene produces a 46.2 kDa protein composed of 418 amino acids.^{[4] [5]} This gene has 8 exons and encodes a multi-pass integral membrane protein localized to the mitochondrial outer membrane.

Function

The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria.^[6] It promotes mitochondrial fission and prevents the formation of hyperfilamentous mitochondria. This protein forms a complex with mitofilin (IMMT) on the inner mitochondrial membrane, independent of MFN2.

Clinical Significance

Mutations in the SLC25A46 gene, inherited in an autosomal recessive manner, cause type 6B hereditary motor and sensory neuropathy. Symptoms include early-onset optic atrophy, progressive visual loss, and peripheral sensorimotor neuropathy manifesting as axonal Charcot-Marie-Tooth disease, with variable age at onset and severity.^{[7] [8]}

Overexpression of this protein causes mitochondrial fragmentation while knockdown of this protein causes mitochondrial hyperfusion and hyperfilamentous mitochondria due to decreased mitochondrial fission. Loss of this gene also has many other effects: premature cellular senescence, impaired cellular respiration, destabilization of the MICOS (mitochondrial contact site and cristae organizing system) complex, loss of and shortened cristae, altered ER morphology, impaired cell migration, and changes in mitochondrial phospholipid composition.

Interactions

This protein interacts with IMMT, a component of the MICOS complex, along with other components of this complex and components of an ER membrane protein complex involved in transferring lipids to mitochondria. Additionally, this protein interacts with SLC7A8, SLC10A1, SLC10A6, FHL3, FUNDC1, linc01142, LEPROTL1, ODF4, VMA21, MFSD14B, PQLC1, HSD17B11, REEP2, REEP4, and TOMM22.^[9] This protein possibly interacts with OPA1 and MFN2.

Further reading

• Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ . Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression . PLOS ONE . 5 . 9 . e12862 . September 2010 . 20877624 . 2943476 . 10.1371/journal.pone.0012862 . 2010PLoSO...512862H . free .
• Palmieri F . The mitochondrial transporter family SLC25: identification, properties and physiopathology . Molecular Aspects of Medicine . 34 . 2–3 . 465–84 . 2013 . 23266187 . 10.1016/j.mam.2012.05.005 .
• Parry HM, Donnelly LA, Van Zuydam N, Doney AS, Elder DH, Morris AD, Struthers AD, Palmer CN, Lang CC . Genetic variants predicting left ventricular hypertrophy in a diabetic population: a Go-DARTS study including meta-analysis . Cardiovascular Diabetology . 12 . 109 . July 2013 . 23879873 . 3729417 . 10.1186/1475-2840-12-109 . free .
• Gao J, Ma Y, Sheng Y, Zuo X, Wang W, Zheng X, Tang H, Tang X, Zhou F, Yang S, Zhang X, Sun L . Association analysis of allergic sensitization susceptibility loci with atopic dermatitis in Chinese population . Journal of Dermatological Science . 80 . 3 . 217–20 . December 2015 . 26464032 . 10.1016/j.jdermsci.2015.09.009 . free .
• Janer A, Prudent J, Paupe V, Fahiminiya S, Majewski J, Sgarioto N, Des Rosiers C, Forest A, Lin ZY, Gingras AC, Mitchell G, McBride HM, Shoubridge EA . SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome . EMBO Molecular Medicine . 8 . 9 . 1019–38 . September 2016 . 27390132 . 5009808 . 10.15252/emmm.201506159 .
• Wan J, Steffen J, Yourshaw M, Mamsa H, Andersen E, Rudnik-Schöneborn S, Pope K, Howell KB, McLean CA, Kornberg AJ, Joseph J, Lockhart PJ, Zerres K, Ryan MM, Nelson SF, Koehler CM, Jen JC . Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia . Brain . 139 . 11 . 2877–2890 . November 2016 . 27543974 . 5840878 . 10.1093/brain/aww212 .
• Steffen J, Vashisht AA, Wan J, Jen JC, Claypool SM, Wohlschlegel JA, Koehler CM . Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria . Molecular Biology of the Cell . 28 . 5 . 600–612 . March 2017 . 28057766 . 5328619 . 10.1091/mbc.E16-07-0545 .

Notes and References

1. Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA, Campeanu IJ, Griffin LB, Groenewald S, Strickland AV, Tao F, Speziani F, Abreu L, Schüle R, Caporali L, La Morgia C, Maresca A, Liguori R, Lodi R, Ahmed ZM, Sund KL, Wang X, Krueger LA, Peng Y, Prada CE, Prows CA, Schorry EK, Antonellis A, Zimmerman HH, Abdul-Rahman OA, Yang Y, Downes SM, Prince J, Fontanesi F, Barrientos A, Németh AH, Carelli V, Huang T, Zuchner S, Dallman JE . 6 . Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder . Nature Genetics . 47 . 8 . 926–32 . August 2015 . 26168012 . 4520737 . 10.1038/ng.3354 .
2. Janer A, Prudent J, Paupe V, Fahiminiya S, Majewski J, Sgarioto N, Des Rosiers C, Forest A, Lin ZY, Gingras AC, Mitchell G, McBride HM, Shoubridge EA . SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome . EMBO Molecular Medicine . 8 . 9 . 1019–38 . September 2016 . 27390132 . 5009808 . 10.15252/emmm.201506159 .
3. Web site: Entrez Gene: Solute carrier family 25 member 46. 2018-08-17.
4. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . 6 . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
5. Web site: SLC25A46 - Solute carrier family 25 member 46. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
6. Palmieri F . The mitochondrial transporter family SLC25: identification, properties and physiopathology . Molecular Aspects of Medicine . 34 . 2–3 . 465–84 . April 2013 . 23266187 . 10.1016/j.mam.2012.05.005 .
7. Web site: SLC25A46 - Solute carrier family 25 member 46 - Homo sapiens (Human) - SLC25A46 gene & protein. www.uniprot.org. en. 2018-08-16.
8. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
9. Web site: SLC25A46 binary interactions found for search term SLC25A46 . IntAct Molecular Interaction Database . EMBL-EBI . 2018-08-18 .