Mithocondrial physiology and calcium signalling partnership: from regulation of differentiation to oncosuppressor activity

In recent years, mitochondria have gained much interest as organelles involved not only in the processes of obtaining energy, but also associated with novel roles in cell physiopathology. These roles range from mitochondria being the site for lipid synthesis, through constituting a buffering system for intracellular calcium, and from being a mediator of reactive oxygen species signalling to a regulator of different cell death types. This group of roles requires a highly regulated system of signalling mechanisms. One of these emerging mechanisms is the communication between the mitochondria and the endoplasmic reticulum. In fact, mitochondria and endoplasmic reticulum are tightly associated, in a region called mitochondria associated membranes, where several signalling events allow continuous communication between the two organelles. Among these signalling events, calcium signalling has been considered of great importance. Advanced techniques of molecular biology allow the development of tools for the investigation of these complex subcellular compartments. Particularly useful are those based on the green fluorescent protein and the calcium sensitive luminescent protein, aequorin. In this work, the aforementioned tools have been used to investigate mitochondrial physiology, especially its communications with the endoplasmic reticulum. Two different cellular events were studied: i) the regulation of apoptosis by a strategic oncosuppressor, p53 and ii) differentiation of oligodendrocytes progenitor cells into adult oligodendrocytes during stress condition generated by cytokines. Performed experiments allowed the describing of the endoplasmic reticulum as a new intracellular localization site of p53, where it increases the luminal calcium concentration, promoting the sensitivity to calcium dependent apoptotic stimuli. Simultaneously, it has been revealed how mitochondria are a target for TNFα in oligodendrocytes progenitors, where it promotes reactive oxygen species production and impairment of the respiratory chain activity, inhibiting cell differentiation without promoting cell death. In conclusion, these approaches reveal completely new relations between mitochondria, calcium signalling and cell physiology, shedding new light on the role for this fascinating organelle

The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux

AbstractThe mitochondrial permeability transition pore (mPTP) has long been known to have a role in mitochondrial calcium (Ca2+) homeostasis under pathological conditions as a mediator of the mitochondrial permeability transition and the activation of the consequent cell death mechanism. However, its role in the context of mitochondrial Ca2+ homeostasis is not yet clear. Several studies that were based on PPIF inhibition or knock out suggested that mPTP is involved in the Ca2+ efflux mechanism, while other observations have revealed the opposite result.The c subunit of the mitochondrial F1/FO ATP synthase has been recently found to be a fundamental component of the mPTP. In this work, we focused on the contribution of the mPTP in the Ca2+ efflux mechanism by modulating the expression of the c subunit. We observed that forcing mPTP opening or closing did not impair mitochondrial Ca2+ efflux. Therefore, our results strongly suggest that the mPTP does not participate in mitochondrial Ca2+ homeostasis in a physiological context in HeLa cells

Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment

Dementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer's disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with "mixed" dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline

Mitophagy in Cardiovascular Diseases

Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes

Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging

Reactive oxygen species (ROS) are highly reactive molecules, mainly generated inside mitochondria that can oxidize DNA, proteins, and lipids. At physiological levels, ROS function as “redox messengers” in intracellular signalling and regulation, whereas excess ROS induce cell death by promoting the intrinsic apoptotic pathway. Recent work has pointed to a further role of ROS in activation of autophagy and their importance in the regulation of aging. This review will focus on mitochondria as producers and targets of ROS and will summarize different proteins that modulate the redox state of the cell. Moreover, the involvement of ROS and mitochondria in different molecular pathways controlling lifespan will be reported, pointing out the role of ROS as a “balance of power,” directing the cell towards life or death

Non Linear Realizations of SU(2)×U(1)SU(2)\times U(1) in the MSSM: Model Independent Analysis and g−2g-2 of WW Bosons

We perform a model-independent analysis of the spontaneously broken phase of an $SU(2)\times U(1)$ supersymmetric gauge theory, by using a non-linear parametrization of the Goldstone sector of the theory. The non-linear variables correspond to an $SL(2,C)$ superfield matrix in terms of which a non-linear Lagrangian can be constructed, and the pattern of supersymmetry breaking investigated. The supersymmetric order parameter is the V.E.V. of the neutral pseudo-Goldstone boson. Some applications of this technique are considered, in relation to the minimal supersymmetric standard model, and to determine the $g-2$ of the $W$-bosons in the limit of large top mass.Comment: 11 page

Safety and differences between direct oral anticoagulants and vitamin K antagonists in the risk of post-traumatic intrathoracic bleeding after rib fractures in elderly patients

Closed chest traumas are frequent consequences of falls in the elderly. The presence of concomitant oral anticoagulant therapy can increase the risk of post-traumatic bleeding even in cases of trauma with non-severe dynamics. There is limited information about the differences between vitamin K antagonists and direct oral anticoagulants in the risk of post-traumatic bleeding. To assess differences in the risk of developing intra-thoracic hemorrhages after chest trauma with at least one rib fracture caused by an accidental fall in patients over 75 years of age taking oral anticoagulant therapy. This study involved data from four emergency departments over two years. All patients on oral anticoagulant therapy and over 75 years of age who reported a closed thoracic trauma with at least one rib fracture were retrospectively evaluated. Patients were divided into two study groups according their anticoagulant therapy. Of the 342 patients included in the study, 38.9% (133/342) were treated with direct oral anticoagulants and 61.1% (209/342) were treated with vitamin K antagonist. A total of 7% (24/342) of patients presented intrathoracic bleeding, while 5% (17/342) required surgery or died as a result for the trauma. Posttraumatic intrathoracic bleeding occurred in 4.5% (6/133) of patients receiving direct oral anticoagulants and 8.6% (18/209) of patients receiving vitamin K antagonist. Logistic regression analysis, revealed no difference in the risk of intrathoracic haemorrhages between the two studied groups. Direct oral anticoagulants therapy presents a risk of post-traumatic intrathoracic haemorrhage comparable to that of vitamin K antagonist therapy