Motor memory: when plans speak louder than actions

A new study demonstrates that separate motor memories can be learned and remembered for two physically identical movements, provided that those movements have different goals.     

Mitochondria and cell death

Mitochondria play a central role in both apoptosis and necrosis through the opening of the mitochondrial permeability transition pore (MPTP). This is thought to be formed through a Ca(2+)-triggered conformational change of the adenine nucleotide translocase (ANT) bound to matrix cyclophilin-D and we have now demonstrated this directly by reconstitution of the pure components. Opening of the MPTP causes swelling and uncoupling of mitochondria which, unrestrained, leads to necrosis. In ischaemia/reperfusion injury of the heart we have shown MPTP opening directly. Recovery of hearts correlates with subsequent closure, and agents that prevent opening or enhance closure protect from injury. Transient MPTP opening may also be involved in apoptosis by initially causing swelling and rupture of the outer membrane to release cytochrome c (cyt c), which then activates the caspase cascade and sets apoptosis in motion. Subsequent MPTP closure allows ATP levels to be maintained, ensuring that cell death remains apoptotic rather than necrotic. Apoptosis in the hippocampus that occurs after a hypoglycaemic or ischaemic insult is triggered by this means. Other apoptotic stimuli such as cytokines or removal of growth factors also involve mitochondrial cyt c release, but here there is controversy over whether the MPTP is involved. In many cases cyt c release is seen without any mitochondrial depolarization, suggesting that the MPTP does not open. Recent data of our own and others have revealed a specific outer-membrane cyt c-release pathway involving porin that does not release other intermembrane proteins such as adenylate kinase. This is opened by pro-apoptotic members of the Bcl-2 family such as BAX and prevented by anti-apoptotic members such as Bcl-X(L). Our own data suggest that this pathway may interact directly with the ANT in the inner membrane at contact sites.     

Mitochondria mediated cell death in diabetes

Mitochondrial dysfunction plays a role in the pathogenesis of a wide range of diseases that involve disordered cellular fuel metabolism and survival/death pathways, including neurodegenerative diseases, cancer and diabetes. Cytokine, virus recognition and cellular stress pathways converging on mitochondria cause apoptotic and/or necrotic cell death of β-cells in type-1 diabetes. Moreover, since mitochondria generate crucial metabolic signals for glucose stimulated insulin secretion (GSIS), mitochondrial dysfunction underlies both the functional derangement of GSIS and (over-nutrition) stress-induced apoptotic/necrotic β-cell death, hallmarks of type-2 diabetes. The apparently distinct mechanisms governing β-cell life/death decisions during the development of diabetes provide a remarkable example where remote metabolic, immune and stress signalling meet with mitochondria mediated apoptotic/necrotic death pathways to determine the fate of the β-cell. We summarize the main findings supporting such a pivotal role of mitochondria in β-cell death in the context of current trends in diabetes research.     

Mitochondria: Joining forces to thwart cell death

Mitochondria are highly dynamic organelles that undergo constant cycles of fusion and fission. An additional level of regulation of mitochondrial function, which is particularly important in neurons, is their active transport along microtubules. Recent evidence suggests that the mitochondrial fusion/fission machinery as well as the molecular motors responsible for their movement constitute powerful regulatory control points that directly impact metabolism and regulation of cell death. This is true for not only apoptosis, but also for excitotoxicity where calcium overload is a major component of the cell death process. In this review, we will describe the molecular mechanisms regulating fusion and fission and how this impinges on cell survival in the context of acute neuronal injury.     

Mitochondria in cell life, death and disease

In animal cell, mitochondria are the main sites of the synthesis of ATP required for cell functioning and survival. On the other hand, mitochondria play a key role in initiating cell programmed death (apoptosis). In addition, defects in the mitochondrial genome and in the nuclear genome encoding mitochondrial proteins may result in malfunctioning of these organelles and, as result, in diseases of the whole organism. This article contains basic information on the functioning of oxidative phosphorylation and on mitochondrial production of reactive oxygen species. It also describes initiation of apoptosis at the mitochondrial level. Finally, it briefly presents some most common genetic defects responsible for "mitochondrial diseases".     

Mitochondria,oxidative stress and cell death

In addition to the well-established role of the mitochondria in energy metabolism, regulation of cell death has recently emerged as a second major function of these organelles. This, in turn, seems to be intimately linked to their role as the major intracellular source of reactive oxygen species (ROS), which are mainly generated at Complex I and III of the respiratory chain. Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death. Mitochondria-generated ROS play an important role in the release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and apoptosis. Cytochrome c release occurs by a two-step process that is initiated by the dissociation of the hemoprotein from its binding to cardiolipin, which anchors it to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and results in an increased level of “free” cytochrome c in the intermembrane space. Conversely, mitochondrial antioxidant enzymes protect from apoptosis. Hence, there is accumulating evidence supporting a direct link between mitochondria, oxidative stress and cell death.     

Mitochondria in cell death: novel targets for neuroprotection and cardioprotection

Post-mitotic neurons and heart muscle cells undergo apoptotic cell death in a variety of acute and chronic degenerative diseases. The intrinsic pathway of apoptosis involves the permeabilization of mitochondrial membranes, which leads to the release of protease and nuclease activators, and to bioenergetic failure. Mitochondrial permeabilization is induced by a variety of pathologically relevant second messengers, including reactive oxygen species, calcium, stress kinases and pro-apoptotic members of the Bcl-2 family. Several pharmacological agents act on mitochondria to prevent the permeabilization of their membranes, thereby inhibiting apoptosis. Such agents include inhibitors of the permeability transition pore complex (in particular ligands of cyclophilin D), openers of mitochondrial ATP-sensitive or Ca(2+)-activated K(+) channels, and proteins from the Bcl-2 family engineered to cross the plasma membrane. In addition, manipulations that modulate the expression or activity of mitochondrial uncoupling proteins can prevent the death of post-mitotic cells. Such agents hold promise for use in clinical neuroprotection and cardioprotection.     

Mitochondria,oxidative metabolism and cell death in stroke

Stroke most commonly results from occlusion of a major artery in the brain and typically leads to the death of all cells within the affected tissue. Mitochondria are centrally involved in the development of this tissue injury due to modifications of their major role in supplying ATP and to changes in their properties that can contribute to the development of apoptotic and necrotic cell death. In animal models of stroke, the limited availability of glucose and oxygen directly impairs oxidative metabolism in severely ischemic regions of the affected tissue and leads to rapid changes in ATP and other energy-related metabolites. In the less-severely ischemic “penumbral” tissue, more moderate alterations develop in these metabolites, associated with near normal glucose use but impaired oxidative metabolism. This tissue remains potentially salvageable for at least the first few hours following stroke onset. Early restoration of blood flow can result in substantial recovery of energy-related metabolites throughout the affected tissue. However, glucose oxidation is markedly decreased due both to lower energy requirements in the post-ischemic tissue and limitations on the mitochondrial oxidation of pyruvate. A secondary deterioration of mitochondrial function subsequently develops that may contribute to progression to cell loss. Mitochondrial release of multiple apoptogenic proteins has been identified in ischemic and post-ischemic brain, mostly in neurons. Pharmacological interventions and genetic modifications in rodent models strongly implicate caspase-dependent and caspase-independent apoptosis and the mitochondrial permeability transition as important contributors to tissue damage, particularly when induced by short periods of temporary focal ischemia.     

Mitochondria, calcium and cell death: A deadly triad in neurodegeneration

Mitochondrial Ca²⁺ accumulation is a tightly controlled process, in turn regulating functions as diverse as aerobic metabolism and induction of cell death. The link between Ca²⁺ (dys)regulation, mitochondria and cellular derangement is particularly evident in neurodegenerative disorders, in which genetic models and environmental factors allowed to identify common traits in the pathogenic routes. We will here summarize: i) the current view of mechanisms and functions of mitochondrial Ca²⁺ homeostasis, ii) the basic principles of organelle Ca²⁺ transport, iii) the role of Ca²⁺ in neuronal cell death, and iv) the new information on the pathogenesis of Alzheimer's, Huntington's and Parkinson's diseases, highlighting the role of Ca²⁺ and mitochondria.     

Programmed cell death in plants

The modern concepts of programmed cell death (PCD) in plants are reviewed as compared to PCD (apoptosis) in animals. Special attention is focused on considering the potential mechanisms of implementation of this fundamental biological process and its participants. In particular, the proteolytic enzymes involved in PCD in animals (caspases) and plants (phytaspases) are compared. Emphasis is put on elucidation of both common features and substantial differences of PCD implementation in plants and animals.     

Vacuolar cell death in plants

Vacuolar programmed cell death (PCD) is indispensable for plant development and is accompanied by a dramatic growth of lytic vacuoles, which gradually digest cytoplasmic content leading to self-clearance of dying cells. Our recent data demonstrate that vacuolar PCD critically requires autophagy and its upstream regulator, a caspase-fold protease metacaspase. Furthermore, both components lie downstream of the point of no return in the cell-death pathway. Here we consider the possibilities that i) autophagy could have both cytotoxic and cytoprotective roles in the vacuolar PCD, and ii) metacaspase could augment autophagic flux through targeting an as yet unknown autophagy repressor.     

Mitochondria in plants

The Botanical Review - It is plain from this survey that the opinions of the most competent investigators are in conflict on many important points. The tendency of many workers to dogmatize upon...     

Signalling and cell death in ozone-exposed plants

Experiments with Arabidopsis mutants and sensitive and tolerant pairs in several other species have elucidated the molecular basis of plant ozone sensitivity and ozone lesion development. They have indicated an important role for hormonal signalling in determining the outcome of ozone challenge at the cellular level. The reactive oxygen species (ROS) from ozone degradation can cause either direct necrotic damage or induce the process of programmed cell death. Perception of ozone or ROS from its degradation in the apoplast activates several signal transduction pathways that regulate the responses of the cells to the increased oxidative load. Plant hormones salicylic acid, jasmonic acid, ethylene and abscisic acid are involved in determining the duration and extent of ozone-induced cell death and its propagation. Salicylic acid is required for the programmed cell death, ethylene promotes endogenous ROS formation and lesion propagation, and jasmonic acid is involved in limiting the lesion spreading. Abscisic acid is most likely involved through the regulation of stomata and thus is expected to affect lesion initiation. The roles and interactions of perception of ozone, the immediate downstream responses, hormone biosynthesis and signalling during ozone lesion initiation and formation are reviewed.