Disequilibrium between steady-state Ca²⁺ ion accumulation ratio and membrane potential in mitochondria. Pathway and role of Ca²⁺ ion efflux

The effects of thyroxine treatment, in vivo and in vitro, on Ca2+ efflux from rat liver mitochondria

“…Perhaps the increased rate of Ca2+ efflux following addition of X0 natoms Ca'+/mg protein [20], reflects some destabilization of the mitochondrial membrane with a consequent reduction in the value of A\k. Under such conditions, Ca2+ leaves the mitochondria via a reversal of the Ca2+ influx carrier [21], a process apparently insensitive to ruthenium red [22], (line 4 in, table 2). We have also observed that thyroxine treatment in vivo, appears to protect against the destabilizing effects of the higher Ca2+ levels [2] and to avoid these complicating effects, we have carried out our experiments with <50 natoms Ca'+/mg protein.…”

A fundamental system of cellular energy homeostasis regulated by PGC-1α

“…It is important to note that while some individual components of this pathway have been described in other contexts, such as the release of calcium upon mitochondrial uncoupling (6,(24)(25)(26)(27)(28) and the role of TORC proteins on the PGC-1␣ promoter (47), the merging of these various individual components into a highly integrated regulatory system has not been previously described to our knowledge. Moreover, the striking ability of this system to precisely maintain cellular ATP levels strongly suggests the physiological relevance of this pathway.…”

“…These experiments together indicate that the recovery of ATP levels and cell survival seen after chronic treatment with FCCP requires PGC-1␣. Mitochondria store significant quantities of calcium, and mitochondrial uncoupling is known to cause an increase in intracellular calcium ([Ca 2ϩ ] i ) levels (6,(24)(25)(26)(27)(28). These data are of particular interest because the induction of PGC-1␣ in other contexts has been shown to be regulated by components of the calcium signaling pathways (17,29).…”

NCLX Protein, but Not LETM1, Mediates Mitochondrial Ca2+ Extrusion, Thereby Limiting Ca2+-induced NAD(P)H Production and Modulating Matrix Redox State

“…To achieve such tight regulation, cells are equipped with a number of proteins mediating the transport of Ca 2ϩ across the plasma membrane, the endoplasmic reticulum, and the inner mitochondrial membrane (1). Mitochondria contribute to the shaping of Ca 2ϩ signals through Ca 2ϩ uptake and release (2)(3)(4)(5)(6)(7)(8)(9). At the same time, the associated [Ca 2ϩ ] mt 3 transients act as signals to stimulate energy metabolism.…”

“…Prolonged (pathological) accumulation of Ca 2ϩ in the matrix space can lead to mitochondrial Ca 2ϩ overload, followed by mitochondrial permeability transition pore opening (27)(28)(29), resulting in the activation of cell death signals (30,31). To avoid this transition from stimulatory to detrimental effects of Ca 2ϩ , mitochondria possess two membrane systems to extrude Ca 2ϩ : the Na ϩ /Ca 2ϩ exchanger and the H ϩ /Ca 2ϩ exchanger (5,6). Two mitochondrial inner membrane proteins, namely NCLX (32) (sodium/calcium exchanger protein, mitochondrial; or sodium/ potassium/calcium exchanger 6, mitochondrial; or solute carrier family 24 member 6) and LETM1 (33) (25).…”