Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures

Kovacs, Richard J.; Kardos, Julianna; Heinemann, Uwe; Kann, Oliver

doi:10.1523/jneurosci.4000-04.2005

Cited by 92 publications

(90 citation statements)

References 68 publications

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“…Calcium uniporter was inhibited using Ru360. 6,26 Ru360 with actions specific to mCU activity is known to always reduce mitochondrial Ca 2 þ uptake in various cell types, 6,[27][28][29] leading to decreased or unchanged overall cytoplasmic Ca 2 þ transients during stimulation 13,30 and in some cases increased overall cytoplasmic Ca 2 þ . 6 Calcium uniporter activity was enhanced using Kaempferol, a compound known to increase mitochondrial and overall cytoplasmic Ca 2 þ levels.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Sanganahalli

Hermán

Hyder

et al. 2013

J Cereb Blood Flow Metab

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Local calcium (Ca 2 þ ) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca 2 þ uptake. Mitochondria take up Ca 2 þ through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca 2 þ . Known only in vitro, the in vivo impact of mCU activity may reveal Ca 2 þ -mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca 2 þ sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca 2 þ distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca 2 þ -dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca 2 þ uptake-mediated integrative role of in vivo mitochondria on neocortical activity.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Sanganahalli

Hermán

Hyder

et al. 2013

J Cereb Blood Flow Metab

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“…Therefore mitochondria-specific Ca 2+ indicators (rhod-2) have been used in combination with mitochondria specific markers, such as MitoTracker® Green, to differentiate between mitochondrial and cytosolic rhod-2 fluorescence (Kovacs et al, 2005). The co-localization of both dyes studied by alternating excitation at 488 and 543 nm with a confocal microscope revealed that the dotted rhod-2 fluorescence is colocalized with MitoTracker® Green, and represents intramitochondrial Ca 2+ .…”

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confidence: 99%

“…This approach, in combination with high resolution imaging techniques such as confocal or two-photon microscopy, allows monitoring of mitochondrial Ca 2+ transients at subcellular levels. For example, using rhod-2 or a lower Ca 2+ binding affinity variant rhod-ff (K d 570 nM and K d 19 μM respectively), it was possible to distinguish within CA3 pyramidal neurons a heterogeneous population of mitochondria, which displays different degrees of Ca 2+ uptake during epileptic activity (Kovacs et al, 2005).…”

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confidence: 99%

“…After the images were decomposed into a spatial frequency representation using a Fourier transformation, it was then possible to distinguish between a high frequency spatial signal represented by the mitochondria, and a low frequency spatial signal represented by the cytosol. This method effectively applies a high pass filter function to remove the cytosolic background component and measure changes in intramitochondrial Ca 2+ selectively (Gerencser and Adam-Vizi, 2001;Kovacs et al, 2005). It also allows the detection of "hot spots" and barriers (that limit the diffusion of the mitochondrial Ca 2+ signal) within the mitochondrial areas with more intensive Ca 2+ uptake (Gerencser and Adam-Vizi, 2005).…”

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confidence: 99%

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Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Foster

Galeffi

Gerich

et al. 2006

Progress in Neurobiology

164

135

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Mitochondria are critical for cellular ATP production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca 2+ levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. Among the techniques discussed are the uses of classic imaging techniques such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multi-photon imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

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“…This study, performed in chondrocytes following a mechanical insult, is also the first to show that dantrolene (RyR inhibitor) is able to prevent mitochondrial depolarization. Ru360 (a uniport transporter inhibitor) has been reported to inhibit mitochondrial depolarization in neurons (69). Much work is still needed to determine the role of these channels in chondrocytes subjected to physiologic mechanical stimulation.…”

mentioning

confidence: 99%

Calcium signaling leads to mitochondrial depolarization in impact‐induced chondrocyte death in equine articular cartilage explants

Huser¹,

Davies²

2007

Arthritis & Rheumatism

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Objective. Chondrocyte apoptosis is an important factor in the progression of osteoarthritis. This study aimed to elucidate the mechanisms involved upstream of caspase 9 activation and, in particular, calcium signaling and mitochondrial depolarization.Methods. Articular cartilage explants obtained from healthy horses were subjected to a single impact load (500-gm weight dropped from a height of 50 mm) and cultured in vitro for up to 48 hours. Chondrocyte death was quantified by the TUNEL method. Release of proteoglycans was determined by the dimethylmethylene blue assay. Weight change was measured, and mitochondrial depolarization was determined using JC-1 staining. To assess the role of calcium signaling in impact-induced chondrocyte death, explants were preincubated in culture medium containing various concentrations of calcium. Inhibitors were used to assess the role of individual signaling components in impactinduced chondrocyte death.Results. Calcium quenching, inhibitors of calpains, calcium/calmodulin-regulated kinase II (CaMKII), and mitochondrial depolarization reduced impact-induced chondrocyte death after 48 hours in culture. Transient mitochondrial depolarization was observed 3-6 hours following a single impact load. Mitochondrial depolarization was prevented by calcium quenching, inhibitors of calpain, CaMKII, permeability transition pore formation, ryanodine receptor, and the mitochondrial uniport transporter. Cathepsin B did not appear to be involved in impact-induced chondrocyte death. The calpain inhibitor prevented proteoglycan loss, but the percentage weight gain and proteoglycan loss were unaffected by all treatments used.Conclusion. Following a single impact load, calcium is released from the endoplasmic reticulum via the ryanodine receptor and is taken up by the mitochondria via the uniport transporter, causing mitochondrial depolarization and caspase 9 activation. In addition, calpains and CaMKII play important roles in causing mitochondrial depolarization.

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Mitochondrial Calcium Ion and Membrane Potential Transients Follow the Pattern of Epileptiform Discharges in Hippocampal Slice Cultures

Cited by 92 publications

References 68 publications

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Calcium signaling leads to mitochondrial depolarization in impact‐induced chondrocyte death in equine articular cartilage explants

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