ABCC6 localizes to the mitochondria-associated membrane.
BACKGROUND
Mutations of the orphan transporter ABCC6 (ATP-binding cassette, subfamily C, member 6) cause the connective tissue disorder pseudoxanthoma elasticum. ABCC6 was thought to be located on the plasma membrane of liver and kidney cells.


OBJECTIVE
Mouse systems genetics and bioinformatics suggested that ABCC6 deficiency affects mitochondrial gene expression. We therefore tested whether ABCC6 associates with mitochondria.


RESULTS
We found ABCC6 in crude mitochondrial fractions and subsequently pinpointed its localization to the purified mitochondria-associated membrane fraction. Cell-surface biotinylation in hepatocytes confirmed that ABCC6 is intracellular. Abcc6-knockout mice demonstrated mitochondrial abnormalities and decreased respiration reserve capacity.


CONCLUSIONS
Our finding that ABCC6 localizes to the mitochondria-associated membrane has implications for its mechanism of action in normal and diseased states.
Department of Medicine, Human Genetics, Microbiology, Immunology and Molecular Genetics, 3730 MRL UCLA, Los Angeles, CA 90095-1679, USA.
Lisa J
LJ
Martin
Edward
E
Lau
Harpreet
H
Singh
Laurent
L
Vergnes
Elizabeth J
EJ
Tarling
Margarete
M
Mehrabian
Imran
I
Mungrue
Sheila
S
Xiao
Diana
D
Shih
Lawrence
L
Castellani
Peipei
P
Ping
Karen
K
Reue
Enrico
E
Stefani
Thomas A
TA
Drake
Kristina
K
Bostrom
Aldons J
AJ
Lusis
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D002458:Cell Fractionation; D019069:Cell Respiration / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D050259:Genes, Mitochondrial / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011561:Pseudoxanthoma Elasticum / Q000235:genetics / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse