The mitochondrial permeability transition.

It has been firmly established that the rapid uptake of Ca2+ by mitochondria from a wide range of sources is mediated by a uniporter which permits transport of the ion down its electrochemical gradient. Several mechanisms of Ca2+ efflux from mitochondria have also been extensively discussed in the literature. Energized mitochondria must expend a significant amount of energy to transport Ca2+ against its electrochemical gradient from the matrix space to the external space. Two separate mechanisms have been found to mediate this outward transport: a Ca2+/nNa+ exchanger and a Na(+)-independent efflux mechanism. These efflux mechanisms are considered from the perspective of available energy. In addition, a reversible Ca2(+)-induced increase in inner membrane permeability can also occur. The induction of this permeability transition is characterized by swelling of the mitochondria, leakiness to small ions such as K+, Mg2+, and Ca2+, and loss of the mitochondrial membrane potential. It has been suggested that the permeability transition and its reversal may also function as a mitochondrial Ca2+ efflux mechanism under some conditions. The characteristics of each of these mechanisms are discussed, as well as their possible physiological functions.

Mechanisms by which mitochondria transport calcium.

In the course of evolution, Ca2+ has emerged as the most versatile intracellular messenger. Its concentration within cells is controlled by reversible binding to specific classes of proteins that act as Ca2+ sensors to decode its information before passing it on to targets. The decoding operation is based on specific conformational changes in the sensor proteins. Other proteins intrinsic to membranes simply control Ca2+ concentration without processing its message, by transporting it across membrane boundaries. They are located in the plasma membrane and in the membranes of the organelles (the endo(sarco)plasmic reticulum, the mitochondria, the nuclear envelope), which play distinctive roles in the cellular homeostasis of Ca2+. Ca2+ is an ambivalent signaling agent. It carries information to virtually all processes important to cell life (e.g., it couples excitation to contraction, secretion, gene transcription, and controls enzyme activity through protein phosphorylation-dephosphorylation), but also transmits signals that promote the programmed demise of cells. When escaping control, Ca2+ also precipitates toxic cell death.

Generation, control, and processing of cellular calcium signals.

Mitochondrial calcium transport.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2880%2980806-4

Mitochondrial calcium transport

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2879%2980850-9

The resolution of calcium fluxes in heart and liver mitochondria using the lanthanide series

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2878%2980990-9

The effect of phosphoenolpyruvate on the retention of calcium by liver mitochondria

The ability of mitochondria to accumulate large amounts of Ca*+ via a specific carrier in the inner membrane is extensively documented [ 1,2]. The release of Ca2+ from mitochondria ofheart and some other excitable tissues probably occurs via a second carrier, that exchanges Na’ for Ca2+ [3,4]. The mechanism of Ca2+ release from other mitochondria that lack the Na+-Ca2+ exchange, e.g., liver is obscure. Some [S-7] have presented evidence for a second Ca2+ carrier in liver mitochondria, albeit not exchanging Na+, which catalyses release, whereas others [8] have concluded that efflux occurs by reversal of the influx process. In addition, considerable attention has been given to the release of Ca2+ from mitochondria by exogenously added phosphoenolpyruvate (PEP) [9-l 11. However, whether or not the phenomenon of the PEP-induced release of Ca2+ has the qualities of a physiological release mechanism, has not been investigated thorougly. This is the subject of the present paper. In particular, it is shown that the phenomenon is associated with a collapse of the electrical potential difference across the inner membrane, which permits release of Ca2+ via reversal of the energy-linked influx process.

Mitochondria contain 2 separate pathways for Ca 2+ transport. One is used for the uptake, and it consists of an electrogenic uniporter driven by the membrane potential generated by respiration, and inhibited by ruthenium red. The other route is used for the release of Ca 2+ , and has so far been identified and characterized in mitochondria from heart, brain, endocrine tissues, exocrine tissues, and skeletal muscles. It consists of a ruthenium red-insensitive system, which specifically exchanges Ca 2+ for Na + . In other mitochondrial types (liver, kidney, lung), the Na + -activated release route is absent. The available evidence, however, suggests separate pathways for Ca 2+ uptake and release also in these mitochondria. The simultaneous operation of the uptake and release routes results in the continuous cycling of Ca 2+ across the inner mitochondrial membrane.

M. Crompton

Papers

The resolution of calcium fluxes in heart and liver mitochondria using the lanthanide series

The effect of phosphoenolpyruvate on the retention of calcium by liver mitochondria

The effect of phosphoenolpyruvate on the retention of calcium by liver mitochondria

THE CYCLING OF Ca2+ ACROSS THE INNER MITOCHONDRIAL MEMBRANE