Increased, Intracellular Calcium overload leads to N/A, Mitochondrial dysfunction 1

One of the mitochondrial functions is to buffer intracellular Ca2+ levels facilitating the maintenance of Ca2+ homeostasis in the cell. In the case of Ca2+ overload, mitochondria are not able to buffer the excess of Ca2+ that leads to mitochondrial dysfunction measured by the increased generation of reactive oxygen species (ROS), triggering mitochondrial permeability transition pore opening (Choi et al.,2013) and reduced ATP production (reviewed in Gleichmann and Mattson, 2011).

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

It was established that the dendritic calcium levels could underlie the differential vulnerability of C57BL/6 (resistant to kainite excitotoxicity) and C57BL/10 strains (vulnerable) mice to triggered neuronal degeneration induced by increased Ca2+ levels (Shuttleworth and Connor, 2001). A striking difference was found in dendrite calcium responses in hippocampus after kainate exposure of C57BL/6 (resistant to kainite excitotoxicity) and C57BL/10 strains (vulnerable). Ca2+ signals in distal dendrites were large in C57BL/10 neurons, and, if a threshold concentration of 1.5 uM was reached, a region of sustained high Ca2+ was established in the distal dendritic tree. This region then served as an initiation site for a degenerative cascade, producing high Ca2+ levels that slowly spread to involve the entire neuron and led to neuronal cell death. Dendritic Ca2+ signals in C57BL/6 neurons were much smaller and did not trigger these propagating secondary responses. Neurons from both strains had similar membrane properties and responded to kainate with intense action potential firing. Degenerative Ca2+ responses were seen in both strains if soma calcium level was above 1.5 uM serving as a threshold that if exceeded triggered excitotoxic neuronal cell death (Shuttleworth and Connor, 2001).

DomA toxicosis in California sea lions (CSLs, Zalophus californianus) is accompanied by increased expression of markers of oxidative stress such as malondialdehyde (MDA) and 3-nitrotyrosine (NT) in neurons (Madl et al., 2014).

In Atlantic salmon (Salmo salar), the cognition function has been investigated after exposure to sub-lethal doses of DomA (6 mg DA/kg bw). In addition, 14C-2-deoxyglucose has been injected i.m. to measure brain metabolic activity by autoradiography. The three brain regions investigated telencephalon, optic tectum and cerebellum have demonstrated a clear increase of metabolic activity in DomA exposed brains (Bakke and Horsberg, 2007).