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induces BiP/GRP78 expression and reduces the capacity to undergo
apoptosis in response to staurosporine, thapsigargin or anti-FAS antibodies
( Simmen et al., 2005 ). Sig-1R is a chaperone protein that is highly expressed
in several tumor cell lines ( Aydar et al., 2006 ). Pharmacological agonists of
Sig-1R function promote resistance to apoptosis ( Spruce et al., 2004 ). This
protein is found in MAMs, where it interacts with BiP/GRP78 ( Hayashi
and Su, 2007 ). Upon ER stress, Sig-1R dissociates from BiP/GRP78 and
promotes mitochondrial calcium uptake via the inositol triphosphate
receptor. Overexpression of Sig-1R counteracts ER stress-induced apop-
tosis ( Hayashi and Su, 2007 ). This protein may also play an important role
in cancer progression. In physiological conditions, Sig-1R induces mito-
chondrial calcium uptake, while its overexpression results in resistance to
apoptotic stimuli ( Hayashi and Su, 2007 ). Mitofusin 2 (Mfn2) is involved in
mitochondrial dynamics and fusion of the outer mitochondrial membrane.
Mfn2 is localized in MAMs, where it participates in the transfer of cal-
cium between ER and the mitochondria. Mfn2 loss-of-function increases
ER and mitochondria calcium levels but decreases mitochondrial calcium
uptake ( de Brito and Scorrano, 2008 ). On the other hand, decreased levels
of Mfn2 enhance proliferation while its overexpression induces cell cycle
arrest in rat vascular smooth muscle cells ( Chen et al., 2004 ).
Available data suggest that ER-mitochondria coupling is essential to
regulate proliferation or apoptosis. In addition, proteins involved in ER
morphology may also impact ER-mitochondria coupling. A recent study
revealed an interesting link between ER stress and mitochondrial adap-
tation in an animal model of pulmonary arterial hypertension (PAH), a
pathology characterized by proliferation and resistance of smooth muscle
cells to death signals ( Sutendra et al., 2011 ). These authors further dem-
onstrated that NOGO-B, a reticulon-4 isoform that participates in the
formation and maintenance of ER shape, regulates mitochondrial activ-
ity in hypoxia. NOGO-B protein levels are increased in smooth muscle
cells isolated from PAH patients subjected to hypoxia. NOGO-B upregu-
lation under those conditions is dependent upon ATF6 activity. In addi-
tion, NOGO-B upregulation leads to the disruption of ER-mitochondria
coupling. This loss causes a decrease in lipid and calcium transfer from
the ER to the mitochondria, which impairs mitochondrial OXPHOS, and
decreases Krebs cycle intermediates. Under these conditions, HIF-1α is
activated and, subsequently, the glycolytic and antiapoptotic programs. This
report suggests that ER-mitochondria uncoupling promotes an adaptive
metabolic response, similar to the Warburg effect in proliferating cells. Based
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