Ca2+ is a ubiquitous second messenger that can be released from intracellular Ca2+ stores in the endoplasmic reticulum (ER) through ryanodine receptor (RyR) channels and IP3 receptor (IP3R) channels. The released Ca2+ is a cytosolic Ca2+ signal, which can regulate diverse cellular functions. Ca2+ clearance mechanisms are important because they directly affect the spatio-temporal characteristic of the Ca+ signal. Mitochondria have the capacity to take up cytosolic Ca2+ and are thus a key Ca2+ clearance mechanism. Mitochondrial Ca2+ uptake impacts cellular physiology in two ways. The first is the effect of mitochondria in sculpting cytosolic Ca2+ signals. The second is the effect of Ca2+ uptake on energy production by the mitochondria. In the present studies, I examined the relationship between mitochondria and Ca2+ released from the ER through both RyRs and IP3Rs in vagal sensory neurons. In the course of the work, diverse techniques were used, including patch clamp electrophysiology, focal photolysis of caged molecules to achieve intracellular generation of second messengers, as well as confocal imaging of fluorescent indicators of cytosolic and mitochondrial Ca2+ concentration, fluorescent organellar stains, and fluorescent indicators of mitochondrial membrane potential. The key findings of the studies are: 1) Mitochondria in the sub-plasma-membrane region preferentially take up Ca2+ released from ER through RyR channelscompared with mitochondria in the cell interior. 2) When sub-plasma-membrane RyRs are activated locally, the resulting cytosolic Ca2+ signal decays back to baseline more slowly than Ca2+ signals resulting from activation of RyRs in the cell interior; this is a consequence of differential Ca2+ handling by mitochondria near the plasma membrane. 3) Preferential Ca2+ uptake by sub-plasma-membrane mitochondria is a consequence of these mitochondria having a more hyperpolarized membrane potential. 4) Upon metabotropic activation of IP3 production and consequent IP3R-mediated Ca2+ release, sub-plasma-membrane mitochondria show preferential Ca2+uptake. 5) Increase in mitochondrial Ca2+concentration following uptake drives increased NADH production.