SLC25A46

{{Short description|Protein-coding gene in the species Homo sapiens}}

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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder | journal = Nature Genetics | volume = 47 | issue = 8 | pages = 926–32 | date = August 2015 | pmid = 26168012 | pmc = 4520737 | doi = 10.1038/ng.3354 }}{{cite journal | vauthors = 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 | title = SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome | journal = EMBO Molecular Medicine | volume = 8 | issue = 9 | pages = 1019–38 | date = September 2016 | pmid = 27390132 | pmc = 5009808 | doi = 10.15252/emmm.201506159 }} Mutations in this gene result in neuropathy and optic atrophy.{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/91137|title=Entrez Gene: Solute carrier family 25 member 46|access-date=2018-08-17}}{{PD-notice}}

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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}{{cite web|url=https://amino.heartproteome.org/web/protein/Q8N5M1|title=SLC25A46 - Solute carrier family 25 member 46|work=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} This gene has 8 exons and encodes a multi-pass integral membrane protein localized to the mitochondrial outer membrane.{{OMIM|610826|solute carrier family 25, member 46; SLC25A46}}

Function

The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria.{{cite journal | vauthors = Palmieri F | title = The mitochondrial transporter family SLC25: identification, properties and physiopathology | journal = Molecular Aspects of Medicine | volume = 34 | issue = 2–3 | pages = 465–84 | date = April 2013 | pmid = 23266187 | doi = 10.1016/j.mam.2012.05.005 }} 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.{{Cite web|url=https://www.uniprot.org/uniprot/Q96AG3|title=SLC25A46 - Solute carrier family 25 member 46 - Homo sapiens (Human) - SLC25A46 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-16}}{{CC-notice|cc=by4}}{{cite journal | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}

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.{{Cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=SLC25A46 | title = SLC25A46 binary interactions found for search term SLC25A46 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-18 }} This protein possibly interacts with OPA1 and MFN2.

SLC25A46

Structure

Function

Clinical Significance

Interactions

References

Further reading