(from the application): Mitochondria control and respond to changes in intracellular Ca release. In frog oocytes, energization of mitochondria increases Ca wave amplitude, velocity and interwave periods of Ca activity stimulated by inositol 1,4,5-trisphosphate. In liver cells and astrocytes, de-energization leads to increases in Ca wave amplitude and velocity. These affects can be attributed to the magnitude of mitochondrial Ca sequestration and whether or not Ca dependent activation or inactivation of inositol 1,4,5-trisphosphate receptors is predominantly affected. Mitochondrial respiration also increases in response to Ca uptake, due to the stimulation of Ca sensitive enzymes within the citric acid cycle. Given the reported decrease in mitochondrial function with age, this proposal is focused on the repercussions for Ca signaling.
The specific aims are: 1) To characterize age-dependent mitochondrial Ca signaling in astrocytes; 2) To determine how Ca signaling is modulated by dysfunctional mitochondria generated in animal models with decreased mtDNA integrity and with altered oxidative damage; and 3) To examine insitu the functional properties of exogenous mitochondria, isolated from animal models and transplanted into Xenopus oocytes. Single photon and two-photon fluorescent imaging will be used to measure Ca, membrane potential and respiration in these experiments. The significance of these studies is three-fold. First, control of intracellular Ca is central to many cell signaling pathways including cell growth, differentiation and death. Second, mitochondria are known to play key regulatory roles in neuronal excitotoxicity and apoptosis. Finally, dysfunctional mitochondria, which accumulate with age and/or oxidative stress are promising targets for therapeutic intervention.
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