1,721,052 research outputs found
Mithocondrial physiology and calcium signalling partnership: from regulation of differentiation to oncosuppressor activity
Full text linkIn 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
Metabolism and HSC fate: what NADPH is made for
No full textMitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders
Metabolism as master of hematopoietic stem cell fate
No full textHSCs have a fate choice when they divide; they can self-renew, producing new HSCs, or produce daughter cells that will mature to become committed cells. Technical challenges, however, have long obscured the mechanics of these choices. Advances in flow-sorting have made possible the purification of HSC populations, but available HSC-enriched fractions still include substantial heterogeneity, and single HSCs have proven extremely difficult to track and observe. Advances in single-cell approaches, however, have led to the identification of a highly purified population of hematopoietic stem cells (HSCs) that make a critical contribution to hematopoietic homeostasis through a preference for self-renewing division. Metabolic cues are key regulators of this cell fate choice, and the importance of controlling the population and quality of mitochondria has recently been highlighted to maintain the equilibrium of HSC populations. Leukemic cells also demand tightly regulated metabolism, and shifting the division balance of leukemic cells toward commitment has been considered as a promising therapeutic strategy. A deeper understanding of precisely how specific modes of metabolism control HSC fate is, therefore, of great biological interest, and more importantly will be critical to the development of new therapeutic strategies that target HSC division balance for the treatment of hematological disease
Mitochondrial control of hematopoietic stem cell balance and hematopoiesis
No full textHematopoietic stem cells (HSCs) are stem cells from mesodermal derivation that reside in bone marrow and provide blood cells for the whole life of an adult individual, through a process called hematopoiesis. The long lasting support of HSCs for hematopoiesis is permitted by the fine regulation of quiescence and division output. Exit from the quiescent state is to produce a committed and/or stem daughter cells, in an event defined asymmetric or symmetric division. A deregulation in the proportion between asymmetric and symmetric divisions is critical in the appearance of hematological disorders ranging from bone marrow failure to hematological malignancies. Over the past years, several studies have indicated how the metabolism of HSCs is determinant in the regulation of HSC quiescence and commitment process. A metabolism shifted to the glycolytic pathway promotes HSCs quiescence and sustainment of hematopoiesis. Boosting mitochondrial respiration promotes the stem cell commitment followed by stem pool exhaustion, and minimal mitochondrial activity is required to maintain the HSCs quiescence. In the present review are discussed the most recent advances in comprehension of the roles of mitochondria in the hematopoiesis and in the division balance. © 2015, Higher Education Press and Springer-Verlag Berlin Heidelberg
Novel frontiers in calcium signaling: A possible target for chemotherapy
No full textp53, Intravital imaging, Cell death and apoptosis, Cancer, Calcium signalin
Mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death
No full textSince its discovery in the 1970s, the mitochondrial permeability transition has been proposed to be a strategic regulator of cell death. Intense research efforts have focused on elucidating the molecular components of the mitochondrial permeability transition because this knowledge may help to better understand and treat various pathologies ranging from neurodegenerative and cardiac diseases to cancer. In the case of cancer, several studies have revealed alterations in the activity of the mitochondrial permeability transition pore (mPTP) and have determined its regulatory mechanism; these studies have also suggested that suppression of the activity of the mPTP, rather than its inactivation, commonly occurs in solid neoplasms. This review focuses on the most recent advances in understanding mPTP regulation in cancer and highlights the ability of the mPTP to impede the mechanisms of cell death
The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux
No full textAbstractThe 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
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