Mitochondria are central to energy metabolism as the source of much of the cell's ATP, as well as being a hub for cellular Ca2+ signaling. Mitochondrial Ca2+ is a positive effector of ATP synthesis, yet Ca2+ overload can lead to mitochondrial dysfunction and cell death. Moreover, Ca2+ uptake by mitochondria is involved in shaping cellular Ca2+ dynamics by regulating the concentrations of Ca2+ within microdomains between mitochondria and sarco/endoplasmic reticulum and plasma membrane Ca2+ transporters. Reactive oxygen species (ROS) generated as a consequence of ATP production in the mitochondria are important for cellular signaling, yet contribute to oxidative stress and cellular damage. ROS regulate the activity of redox sensitive enzymes and ion channels within the cell, including Ca2+ channels. For both Ca2+ and ROS, a delicate balance exists between the beneficial and detrimental effects on mitochondria. In this review we bring together current data on mitochondrial Ca2+ uptake, ROS generation, and redox modulation of Ca2+ transport proteins. We present a model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains.

/pdf/crosstalk-signaling-between-mitochondrial-ca2-and-ros-4rhm5wi9az.pdf

Crosstalk signaling between mitochondrial Ca2+ and ROS.

The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.

SEA0400, a Novel and Selective Inhibitor of the Na+-Ca2+ Exchanger, Attenuates Reperfusion Injury in the in Vitro and in Vivo Cerebral Ischemic Models

Mitochondria are an important source of reactive oxygen species (ROS) formed as a side product of oxidative phosphorylation. The main sites of oxidant production are complex I and complex III, wher...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00217.2006

Mitochondrial reactive oxygen species and Ca2+ signaling

In the last two decades, there has been a growing interest in unraveling the role that the Na+/Ca2+ exchanger (NCX) plays in the function and regulation of several cellular activities. Molecular biology, electrophysiology, genetically modified mice, and molecular pharmacology have helped to delve deeper and more successfully into the physiological and pathophysiological role of this exchanger. In fact, this nine-transmembrane protein, widely distributed in the brain and in the heart, works in a bidirectional way. Specifically, when it operates in the forward mode of operation, it couples the extrusion of one Ca2+ ion with the influx of three Na+ ions. In contrast, when it operates in the reverse mode of operation, while three Na+ ions are extruded, one Ca2+ enters into the cells. Different isoforms of NCX, named NCX1, NCX2, and NCX3, have been described in the brain, whereas only one, NCX1, has been found in the heart. The hypothesis that NCX can play a relevant role in several pathophysiological conditions, including hypoxia-anoxia, white matter degeneration after spinal cord injury, brain trauma and optical nerve injury, neuronal apoptosis, brain aging, and Alzheimer's disease, stems from the observation that NCX, in parallel with selective ion channels and ATP-dependent pumps, is efficient at maintaining intracellular Ca2+ and Na+ homeostasis. In conclusion, although studies concerning the involvement of NCX in the pathological mechanisms underlying brain injury during neurodegenerative diseases started later than those related to heart disease, the availability of pharmacological agents able to selectively modulate each NCX subtype activity and antiporter mode of operation will provide a better understanding of its pathophysiological role and, consequently, more promising approaches to treat these neurological disorders.

Pharmacology of Brain Na+/Ca2+ Exchanger: From Molecular Biology to Therapeutic Perspectives

Calcium Microdomains in Aspiny Dendrites

Sensitivity of the synaptic membrane na+/ca2+ exchanger and the expressed ncx1 isoform to reactive oxygen species

Antisense oligonucleotide suppression of Na+/Ca2+ exchanger activity in primary neurons from rat brain

Effects of Antisense Oligonucleotides to the Cardiac Na+/Ca2+ Exchanger on Calcium Dynamics in Cultured Cardiac Myocytes

Publisher Summary This chapter discusses the major elements of the Ca 2+ hypothesis, followed by an overview of the principal neuronal systems responsible for regulating intracellular Ca 2+ and reviews the experimental observations that have been reported with regard to altered Ca 2+ homeostasis in aging neurons. It is suggested that aging-related alterations in Ca 2+ handling mechanisms could serve to make the cells highly vulnerable to metabolic stresses such as ischemia, enhanced free radical production, head trauma, and hyperthermia and, possibly, to the abnormal processing and deposition of amyloid peptides within specific brain regions. The Ca 2+ hypothesis provides a cogent unifying concept that may help explain the cognitive decline that occurs with normal aging in many individuals and the underlying process that sets the stage for the development of late-onset Alzheimer's disease in a very large percentage of the elderly. Many more studies are needed to see if a link can indeed be demonstrated between Ca 2+ dysregulation and impaired behavioral and cognitive performance. If this link is established, it may be possible in the not too distant future to develop means of dampening the impact alterations in these systems have on optimal brain function.

Jana Huschenbett

Papers

Sensitivity of the synaptic membrane na+/ca2+ exchanger and the expressed ncx1 isoform to reactive oxygen species

Antisense oligonucleotide suppression of Na+/Ca2+ exchanger activity in primary neurons from rat brain

Effects of Antisense Oligonucleotides to the Cardiac Na+/Ca2+ Exchanger on Calcium Dynamics in Cultured Cardiac Myocytes

Chapter 6 Neuronal Calcium Regulation in Aging Brain