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 .
[5]
[6]
Mutations in this gene result in
neuropathy and optic atrophy .
[7]
Structure
The SLC25A46 gene is located on the q arm of
chromosome 5 in position 22.1 and spans 27,039 base pairs.
[7] The gene produces a 46.2 kDa protein composed of 418
amino acids .
[8]
[9] This gene has 8
exons and encodes a
multi-pass
integral membrane protein
localized to the mitochondrial outer membrane.
[10]
[11]
[12]
Function
The encoded protein is an orphan transporter involved in lipid transfer from the endoplasmic reticulum to mitochondria.
[13]
[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 .
[5]
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.
[11]
[12]
Overexpression of this protein causes mitochondrial fragmentation while
knockdown of this protein causes
mitochondrial hyperfusion and hyperfilamentous mitochondria due to decreased mitochondrial fission.
[5] 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.
[6]
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.
[11]
[12]
[6] Additionally, this protein interacts with
SLC7A8 ,
SLC10A1 ,
SLC10A6 ,
FHL3 ,
FUNDC1 ,
linc01142 ,
LEPROTL1 ,
ODF4 ,
VMA21 ,
MFSD14B ,
PQLC1 ,
HSD17B11 ,
REEP2 ,
REEP4 , and
TOMM22 .
[14] This protein possibly interacts with
OPA1 and
MFN2 .
[6]
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000164209 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000024259 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
a
b
c 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 .
^
a
b
c
d
e 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 .
^
a
b
"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) . [
permanent dead link ]
^
Online Mendelian Inheritance in Man (OMIM):
solute carrier family 25, member 46; SLC25A46 - 610826
^
a
b
c
"SLC25A46 - Solute carrier family 25 member 46 - Homo sapiens (Human) - SLC25A46 gene & protein" . www.uniprot.org . Retrieved 2018-08-16 .
This article incorporates text available under the
CC BY 4.0 license.
^
a
b
c
"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.
Bibcode :
2010PLoSO...512862H .
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 .