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Mitochondria

The cardiolipin–cytochrome c interaction and the mitochondrial regulation of apoptosis

By | Mitochondria

The cardiolipin–cytochrome c interaction and the mitochondrial regulation of apoptosis

Suzanne L. Iverson and Sten Orrenius

While many studies have focused on cytochrome c release from mitochondria, little attention has been given to the specific interaction between cardiolipin (CL) and cytochrome c, the breaching of which likely represents a critical event in the initiation of mitochondrially mediated apoptosis. Mounting evidence suggests that a decrease in the level of CL affects cytochrome c binding to the inner membrane, thus leading to higher levels of soluble cytochrome c in the mitochondrial intermembrane space. Among the factors known to affect CL levels are thyroid status, plasma concentrations of free fatty acids, Ca2+ dysregulation, and reactive oxygen species (ROS). These factors, especially Ca2+ and ROS, have long been recognized as triggers of cell death and, more recently, as modulators of mitochondrially mediated apoptosis. In this review, we discuss the significance of the disruption of the CL– cytochrome c interaction for cytochrome c release and apoptosis.

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Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming

By | Mitochondria

Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming

Laurence S. Jouaville, Paolo Pinton, Carlo Bastianutto, Guy A. Rutter, and Rosario Rizzuto

In recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca2+ concentration. Here, we analyzed the significance of Ca2+ signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP]m and [ATP]c, respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca2+ signals caused increases in [ATP]m and [ATP]c that depended on two parameters: (i) the amplitude of the Ca2+ rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca2+ elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP]m upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca2+ in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells.

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Mitochondria Modify Exercise-Induced Development of Stem Cell-Derived Neurons in the Adult Brain

By | Mitochondria

Mitochondria Modify Exercise-Induced Development of Stem Cell-Derived Neurons in the Adult Brain

Kathrin Steib, Iris Scha¨ffner, Ravi Jagasia, Birgit Ebert, and D. Chichung Lie

Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise—a strong modifier of adult hippocampal neurogenesis—accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesisdependent hippocampal plasticity.

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Mitochondria Exert a Negative Feedback on the Propagation of Intracellular Ca2+ Waves in Rat Cortical Astrocytes

By | Mitochondria

Mitochondria Exert a Negative Feedback on the Propagation of
Intracellular Ca2+ Waves in Rat Cortical Astrocytes

Eric Boitier, Ruth Rea, and Michael R. Duchen

We have used digital fluorescence imaging techniques to explore the interplay between mitochondrial Ca2+ uptake and physiological Ca2+ signaling in rat cortical astrocytes. A rise in cytosolic Ca2+ ([Ca2+]cyt), resulting from mobilization of ER Ca2+ stores was followed by a rise in mitochondrial Ca2+ ([Ca2+]m, monitored using rhod-2). Whereas [Ca2+]cyt recovered within ~1 min, the time to recovery for [Ca2+]m was ~30 min. Dissipating the mitochondrial membrane potential ( Dcm, using the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone [FCCP] with oligomycin) prevented mitochondrial Ca2+ uptake and slowed the rate of decay of [Ca2+]cyt transients, suggesting that mitochondrial Ca2+ uptake plays a significant role in the clearance of physiological [Ca2+]cyt loads in astrocytes. Ca2+ signals in these cells initiated either by receptor-mediated ER Ca2+ release or mechanical stimulation often consisted of propagating waves (measured using fluo-3). In response to either stimulus, the wave traveled at a mean speed of 22.9 6 11.2 mm/s (n 5 262). This was followed by a wave of mitochondrial depolarization (measured using tetramethylrhodamine ethyl ester [TMRE]), consistent with Ca2+ uptake into mitochondria as the Ca2+ wave traveled across the cell. Collapse of Dcm to prevent mitochondrial Ca2+ uptake significantly increased the rate of propagation of the Ca2+ waves by 50%. Taken together, these data suggest that cytosolic Ca2+ buffering by mitochondria provides a potent mechanism to regulate the localized spread of astrocytic Ca2+ signals.

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Mitochondria and Ca2+ in cell physiology and pathophysiology

By | Mitochondria

Mitochondria and Ca2+ in cell physiology and pathophysiology

M. R. Duchen

There is now a consensus that mitochondria take up and accumulate Ca2+ during physiological [Ca2+]c signalling. This contribution will consider some of the functional consequences of mitochondrial Ca2+ uptake for cell physiology and pathophysiology. The ability to remove Ca2+ from local cytosol enables mitochondria to regulate the [Ca2+] in microdomains close to IP3-sensitive Ca2-release channels. The [Ca2+] sensitivity of these channels means that, by regulating local [Ca2+]c, mitochondrial Ca2+ uptake modulates the rate and extent of propagation of [Ca2+]c waves in a variety of cell types. The coincidence of mitochondrial Ca2+ uptake with oxidative stress may open the mitochondrial permeability transition pore (mPTP). This is a catastrophic event for the cell that will initiate pathways to cell death either by necrotic or apoptotic pathways. A model is presented in which illumination of an intramitochondrial fluorophore is used to generate oxygen radical species within mitochondria. This causes mitochondrial Ca2 loading from SR and triggers mPTP opening. In cardiomyocytes, mPTP opening leads to ATP consumption by the mitochondrial ATPase and so results in ATP depletion, rigor and necrotic cell death. In central mammalian neurons exposed to glutamate, a cellular Ca2+ overload coincident with NO production also causes loss of mitochondrial potential and cell death, but mPTP involvement has proven more difficult to demonstrate unequivocally.

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Cytochrome c Association with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice

By | Mitochondria

Cytochrome c Association with the Inner Mitochondrial Membrane Is Impaired in the CNS of G93A-SOD1 Mice

Ilias G. Kirkinezos, Sandra R. Bacman, Dayami Hernandez, Jose Oca-Cossio, Laura J. Arias,Miguel A. Perez-Pinzon, Walter G. Bradley, and Carlos T. Moraes

A “gain-of-function” toxic property of mutant Cu–Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of thehumanSOD1gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS.Weobserved a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.

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Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit

By | Mitochondria

Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit

Muqing Yi, David Weaver, and György Hajnóczky

itochondria are dynamic organelles in cells. The control of mitochondrial motility by signaling mechanisms and the significance of rapid changes in motility remains elusive. In cardiac myoblasts, mitochondria were observed close to the microtubular array and displayed both short- and long-range movements along microtubules. By clamping cytoplasmic [Ca 2+ ] ([Ca 2+ ] c ) at various levels, mitochondrial motility was found to be regulated by Ca 2+ in the physiological range. Maximal movement was obtained at resting [Ca 2+] c with complete arrest at 1–2+ M. Movement was M fully recovered by returning to resting [Ca 2+]c , and inhibition could be repeated with no apparent desensitization. The inositol 1,4,5-trisphosphate– or ryanodine receptormediated [Ca 2+]c signal also induced a decrease in mitochondrial motility. This decrease followed the spatial and temporal pattern of the [Ca 2+ ] c signal. Diminished mitochondrial motility in the region of the [Ca 2+ ]c rise promotes recruitment of mitochondria to enhance local Ca 2+ buffering and energy supply. This mechanism may provide a novel homeostatic circuit in calcium signaling.

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Cmc1p Is a Conserved Mitochondrial Twin CX9C Protein Involved in Cytochrome c Oxidase Biogenesis

By | Mitochondria

Cmc1p Is a Conserved Mitochondrial Twin CX9C Protein Involved in Cytochrome c Oxidase Biogenesis

Darryl Horn, Hassan Al-Ali, and Antoni Barrientos

Copper is an essential cofactor of two mitochondrial enzymes: cytochrome c oxidase (COX) and Cu-Zn superoxide dismutase (Sod1p). Copper incorporation into these enzymes is facilitated by metallochaperone proteins which probably use copper from a mitochondrial matrix-localized pool. Here we describe a novel conserved mitochondrial metallochaperone-like protein, Cmc1p, whose function affects both COX and Sod1p. In Saccharomyces cerevisiae, Cmc1p localizes to the mitochondrial inner membrane facing the intermembrane space. Cmc1p is essential for full expression of COX and respiration, contains a twin CX9C domain conserved in other COX assembly copper chaperones, and has the ability to bind copper(I). Additionally, mutant cmc1 cells display increased mitochondrial Sod1p activity, while CMC1 overexpression results in decreased Sod1p activity. Our results suggest that Cmc1p could play a direct or indirect role in copper trafficking and distribution to COX and Sod1p.

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The molecular era of the mitochondrial calcium uniporter

By | Mitochondria

The molecular era of the mitochondrial calcium uniporter

Kimberli J. Kamer, and Vamsi K. Mootha

The mitochondrial calcium uniporter is an evolutionarily conserved calcium channel, and its biophysical properties and relevance to cell death, bioenergetics and signalling have been investigated for decades. However, the genes encoding this channel have only recently been discovered, opening up a new ‘molecular era’ in the study of its biology. We now know that the uniporter is not a single protein but rather a macromolecular complex consisting of pore-forming and regulatory subunits. We review recent studies that harnessed the power of molecular biology and genetics to characterize the mechanism of action of the uniporter, its evolution and its contribution to physiology and human disease.

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