Ca2+ Hot Spots on the Mitochondrial Surface Are Generated by Ca2+ Mobilization from Stores, but Not by Activation of Store-Operated Ca2+ Channels

Giacomello, Marta; Drago, Ilaria; Bortolozzi, Mario; Scorzeto, Michele; Gianelle, A.; Pizzo, Paola; Pozzan, Tullio

doi:10.1016/j.molcel.2010.04.003

Cited by 359 publications

(341 citation statements)

References 32 publications

Supporting

Mentioning

305

Contrasting

Unclassified

Order By: Relevance

“…Our data show also that the larger [Ca 2+ ] M increases occur in cell regions close to the nucleus. This is consistent with the data of Giacomello et al [22], which also show a larger accumulation of mitochondria-associated Ca 2+ microdomains close to the nucleus.…”

Section: Discussionsupporting

confidence: 93%

“…Further evidence for this phenomenon was later obtained in other cells [3] and it has been interpreted on the basis of the presence of local Ca 2+ microdomains generated in regions of close apposition of mitochondria and ER, or mitochondria and the plasma membrane. Direct evidence for the presence of these cytosolic [Ca 2+ ] microdomains in the vicinity of mitochondria has been recently provided [16,22]. Our data show also that the larger [Ca 2+ ] M increases occur in cell regions close to the nucleus.…”

Section: Discussionsupporting

confidence: 70%

See 1 more Smart Citation

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

et al. 2012

View full text Add to dashboard Cite

a b s t r a c tAvailable methods to measure mitochondrial [Ca 2+ ] ([Ca 2+ ] M ) include both targeted proteins and fluorescent dyes. Targeted proteins usually report much higher [Ca 2+ ] M values than fluorescent dyes, up to two orders of magnitude. However, we show here that the low-Ca 2+ -affinity dye rhod-5N provides [Ca 2+ ] M values similar to those reported by targeted aequorin, suggesting that the discrepancies are mainly due to the higher Ca 2+ -affinity of the fluorescent dyes used. We find rhod-5N has an apparent in situ intramitochondrial Kd around 0.5 mM. Addition of Ca 2+ buffers containing between 4.5 and 10 M [Ca 2+ ] to permeabilized cells loaded with rhod-5N induced increases in calibrated [Ca 2+ ] M up to the 100 M-1 mM range, which were dependent on mitochondrial membrane potential. Ca 2+ release from mitochondria was largely dependent on [Na + ]. We have then used rhod-5N loaded cells to investigate the [Ca 2+ ] M response to agonist stimulation at the single-cell and subcellular level.The [Ca 2+ ] M peaks induced by histamine varied by nearly 10-fold among different cells, with a mean about 25 M. In the presence of the Ca 2+ uniporter stimulator kaempferol, the [Ca 2+ ] M peaks induced by histamine were also highly variable, and the mean [Ca 2+ ] M peak was 3-fold higher. Simultaneous measurement of cytosolic and mitochondrial [Ca 2+ ] peaks showed little correlation among the heights of the peaks in both compartments. Studying the [Ca 2+ ] M peaks at the subcellular level, we found significant heterogeneities among regions in the same cell. In particular, the [Ca 2+ ] M increase in mitochondrial regions close to the nucleus was more than double that of mitochondrial regions far from the nucleus.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 70%

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

et al. 2012

View full text Add to dashboard Cite

show abstract

“…26 We followed the latter Figure 1 Sensitivity to apoptotic challenges of VDAC-silenced cells. Cells were co-transfected with a fluorescent marker (GFP) and the siRNA of interest.…”

Section: Resultsmentioning

confidence: 99%

VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria

et al. 2011

View full text Add to dashboard Cite

Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca 2 þ loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca 2 þ signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP 3 receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca 2 þ signals to mitochondria in apoptosis.

show abstract

“…2010; Giacomello et al. 2010). During ER stress, calcium can be massively transferred to the mitochondria through these ER‐mitochondria microdomains, or as a consequence of increased cytosolic calcium (Mandic et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

View full text Add to dashboard Cite

Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

show abstract

Ca2+ Hot Spots on the Mitochondrial Surface Are Generated by Ca2+ Mobilization from Stores, but Not by Activation of Store-Operated Ca2+ Channels

Cited by 359 publications

References 32 publications

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

Dynamics of mitochondrial [Ca2+] measured with the low-Ca2+-affinity dye rhod-5N

VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria

Role of endoplasmic reticulum stress in drug‐induced toxicity

Contact Info

Product

Resources

About