Human Molecular Genetics, Vol 8, 2541-2549, Copyright © 1999 by Oxford University Press
J Yao and EA Shoubridge
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency
is an autosomal recessive neurodegenerative disorder caused by mutations in
SURF1. Although SURF1 is ubiquitously expressed, its expression is lower in
brain than in other highly aerobic tissues. All reported SURF1 mutations
are loss of function, predicting a truncated protein (hSurf1) product.
Western blot analysis with anti-hSurf1 antibodies demonstrated a specific
30 kDa protein in control fibroblasts, but no protein in LS patient cells.
Steady-state levels of both nuclear- and mitochondrial-encoded COX subunits
were also markedly reduced in patient cells, consistent with a failure to
assemble or maintain a normal amount of the enzyme complex. An epitope
(FLAG)- tagged hSurf1 was targeted to mito-chondria in COS7 cells and a
mitochondrial import assay showed that the hSurf1 precursor protein (35
kDa) was imported and processed to its mature form (30 kDa) in a membrane
potential-dependent fashion. The protein was resistant to alkaline
carbonate extraction and susceptible to proteinase K digestion in
mitoplasts. Mutant proteins in which the N-terminal transmembrane domain or
central loop were deleted, or the C-terminal transmembrane domain
disrupted, did not accumulate and could not rescue COX activity in patient
cells. Co-expression of the N- and C-terminal transmembrane domains as
independent entities also failed to rescue the enzyme deficiency. These
data demonstrate that hSurf1 is an integral inner membrane protein with an
essential role in the assembly or maintenance of the COX complex and that
insertion of both transmembrane domains in the intact protein is necessary
for function.
ARTICLES
Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency
Montreal Neurological Institute and Department of Human Genetics, McGill University, 3801 University Street, Montreal H3A 2B4, Canada
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