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evidence suggesting the existence of a low-affinity calcium uptake system
questioned the physiological relevance of mitochondria in calcium han-
dling.
For many years, calcium accumulation and protection of the cell against
calcium overload was considered to be the only function of mitochondria
in the control of intracellular calcium metabolism. However, this view was
challenged by observations showing that the activity of pyruvate, isocitrate
and α-ketoglutarate dehydrogenases in permeabilized or homogenized
mitochondria was enhanced by calcium in a direct or an indirect manner
(
McCormack et al., 1990
;
Carafoli, 2010
). Interestingly, agonist-induced
calcium release can lead to improved mitochondrial function as evidenced
by increased ATP production after restoring normal mitochondrial calcium
levels (
Jouaville et al., 1999
). Additionally, also many other mitochondrial
processes, such as fatty acid oxidation, amino acid catabolism, F1-ATPase
manganese superoxide dismutase activity, aspartate and glutamate carrier, as
well as
the adenine-nucleotide translocase activity, are regulated by mito-
chondrial calcium (
McCormack et al., 1990
;
Hayashi et al., 2009
). Moreover,
Cárdenas et al. (2010)
recently showed that basal IP3R activity was required
to control mitochondrial bioenergetics. Absence of this calcium transfer
results in enhanced phosphorylation of pyruvate dehydrogenase and AMPK
activation, which in turn activates autophagy as a prosurvival response. Thus,
constitutive IP3R-mediated calcium release to mitochondria is required for
efficient mitochondrial respiration and maintenance of normal cellular bio-
energetics.
Work from our group performed in HeLa cells demonstrated that early
stages of ER stress increase physical coupling and calcium transfer from ER
to mitochondria, leading to augmented mitochondrial bioenergetics as a
means of adaptive ATP production (
Bravo et al., 2011b
). Physical coupling
between ER and mitochondria is observed upon treatment with differ-
ent ER stressors (tunicamycin, brefeldin A and thapsigargin). However, it
remains unknown to what extent the UPR is involved in these events.
Additionally, a recent study performed in skeletal muscle showed that
adaptation of muscle fibers to acute exercise is mediated by the UPR.
ATF6 is required for the recovery process, involving the coactivation of
PGC1α (
Wu et al., 2011
). Such cross talk between the UPR and PGC1α is
a potential mechanism that may explain how ER stress-mediated control of
mitochondrial metabolism is achieved, given the importance of PGC1α in
mitochondrial biogenesis and fatty acid oxidation (
Koves et al., 2005
;
Safdar
et al., 2011
). Despite such insights, the field of ER-modulated mitochondrial
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