mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

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.

This review provides a selective history of how studies of mitochondrial cation transport (K+, Na+, Ca2+) developed in relation to the major themes of research in bioenergetics. It then covers in some detail specific transport pathways for these cations, and it introduces and discusses open problems about their nature and physiological function, particularly in relation to volume regulation and Ca2+homeostasis. The review should provide the basic elements needed to understand both earlier mitochondrial literature and current problems associated with mitochondrial transport of cations and hopefully will foster new interest in the molecular definition of mitochondrial cation channels and exchangers as well as their roles in cell physiology.

http://agrino.org/skalifourta/Mitochondrial%20Transport%20of%20Cations-%20Channels,%20Exchangers,%20and%20Permeability%20Transition.pdf

Mitochondrial Transport of Cations: Channels, Exchangers, and Permeability Transition

Mitochondrial Cation-Hydrogen Ion Exchange SODIUM SELECTIVE TRANSPORT BY MITOCHONDRIA AND SUBMITOCHONDRIAL PARTICLES

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2878%2980736-4

Ruthenium red sensitive and insensitive calcium transport in rat liver and Ehrlich ascites tumor cell mitochondria.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2875%2980336-X

Ronald S. Cockrell

Papers

Mitochondrial Cation-Hydrogen Ion Exchange SODIUM SELECTIVE TRANSPORT BY MITOCHONDRIA AND SUBMITOCHONDRIAL PARTICLES

Ruthenium red sensitive and insensitive calcium transport in rat liver and Ehrlich ascites tumor cell mitochondria.

Ca2+ transport across plasma and mitochondrial membranes of isolated hepatocytes.

The respiration of brain mitochondria and its regulation by monovalent cation transport.

Calcium transport by Ehrlich ascites cell mitochondria in vitro and in situ.