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.[3] amino acids .[4] [5] exons and encodes a multi-pass integral membrane protein localized to the mitochondrial outer membrane.[6] [7] [8]
Function The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria.[9] [2] 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 .[1]
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.[1] 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.[2]
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.[7] [8] [2] SLC7A8 , SLC10A1 , SLC10A6 , FHL3 , FUNDC1 , linc01142 , LEPROTL1 , ODF4 , VMA21 , MFSD14B , PQLC1 , HSD17B11 , REEP2 , REEP4 , and TOMM22 .[10] OPA1 and MFN2 .[2]
References
↑ 1.0 1.1 1.2 Abrams AJ, Hufnagel RB, Rebelo A, Zanna C, Patel N, Gonzalez MA, et al. (August 2015). "Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder" . Nature Genetics . 47 (8): 926–32. doi :10.1038/ng.3354 . PMC 4520737 PMID 26168012 . ↑ 2.0 2.1 2.2 2.3 2.4 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 (September 2016). "SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome" . EMBO Molecular Medicine . 8 (9): 1019–38. doi :10.15252/emmm.201506159 . PMC 5009808 PMID 27390132 . ↑ 3.0 3.1 "Entrez Gene: Solute carrier family 25 member 46" . Retrieved 2018-08-17 .This article incorporates text from this source, which is in the public domain . ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase" . Circulation Research . 113 (9): 1043–53. doi :10.1161/CIRCRESAHA.113.301151 . PMC 4076475 PMID 23965338 . ↑ "SLC25A46 - Solute carrier family 25 member 46" . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .↑ Online Mendelian Inheritance in Man (OMIM) solute carrier family 25, member 46; SLC25A46 -610826 ↑ 7.0 7.1 7.2 "SLC25A46 - Solute carrier family 25 member 46 - Homo sapiens (Human) - SLC25A46 gene & protein" . www.uniprot.org . Retrieved 2018-08-16 .File:CC-BY-icon-80x15.png CC BY 4.0 license.↑ 8.0 8.1 8.2 "UniProt: the universal protein knowledgebase" . Nucleic Acids Research . 45 (D1): D158–D169. January 2017. doi :10.1093/nar/gkw1099 . PMC 5210571 PMID 27899622 .↑ Palmieri F (April 2013). "The mitochondrial transporter family SLC25: identification, properties and physiopathology" . Molecular Aspects of Medicine . 34 (2–3): 465–84. doi :10.1016/j.mam.2012.05.005 . PMID 23266187 . ↑ "SLC25A46 binary interactions found for search term SLC25A46" . IntAct Molecular Interaction Database . EMBL-EBI. Retrieved 2018-08-18 .
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 (September 2010). "Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression" . PLOS One . 5 (9): e12862. doi :10.1371/journal.pone.0012862 . PMC 2943476 PMID 20877624 . Palmieri F (2013). "The mitochondrial transporter family SLC25: identification, properties and physiopathology". Molecular Aspects of Medicine . 34 (2–3): 465–84. doi :10.1016/j.mam.2012.05.005 . PMID 23266187 . Parry HM, Donnelly LA, Van Zuydam N, Doney AS, Elder DH, Morris AD, Struthers AD, Palmer CN, Lang CC (July 2013). "Genetic variants predicting left ventricular hypertrophy in a diabetic population: a Go-DARTS study including meta-analysis" . Cardiovascular Diabetology . 12 : 109. doi :10.1186/1475-2840-12-109 . PMC 3729417 PMID 23879873 . Gao J, Ma Y, Sheng Y, Zuo X, Wang W, Zheng X, Tang H, Tang X, Zhou F, Yang S, Zhang X, Sun L (December 2015). "Association analysis of allergic sensitization susceptibility loci with atopic dermatitis in Chinese population". Journal of Dermatological Science . 80 (3): 217–20. doi :10.1016/j.jdermsci.2015.09.009 . PMID 26464032 . 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 (September 2016). "SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome" . EMBO Molecular Medicine . 8 (9): 1019–38. doi :10.15252/emmm.201506159 . PMC 5009808 PMID 27390132 . 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 (November 2016). "Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia" . Brain . 139 (11): 2877–2890. doi :10.1093/brain/aww212 . PMC 5840878 PMID 27543974 . Steffen J, Vashisht AA, Wan J, Jen JC, Claypool SM, Wohlschlegel JA, Koehler CM (March 2017). "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. doi :10.1091/mbc.E16-07-0545 . PMC 5328619 PMID 28057766 .
This article incorporates text from the United States National Library of Medicine , which is in the public domain .
This article incorporates text from this source, which is in the public domain.
