1,720,990 research outputs found
The multifaceted mitochondrion: An attractive candidate for therapeutic strategies
No full textMitochondria are considered the powerhouse of the cell and disturbances in mitochondrial functions are involved in several disorders such as neurodegeneration and mitochondrial diseases. This review summarizes pharmacological strategies that aim at modifying the number of mitochondria, their dynamics or the mitochondrial quality-control mechanisms, in several pathological instances in which any of these mechanisms are impaired or abnormal. The interplay between different cellular pathways that involve mitochondria in order to respond to stress is highlighted. Such a high mitochondrial plasticity could be exploited for new treatments
Non-apoptotic roles for death-related molecules: when mitochondria chose cell fate
Full text linkThe decision between death and survival is a difficult phase of a cell life. It may depend on the intensity of a stress stimulus, on the presence of invasive pathogens, or on specific signals from neighbouring cells. Death-related molecules are being shown to possess different, and sometimes opposite roles, which they play also according to a number of environmental clues. In this review, we will analyse some of these molecules and their roles, with particular regard to mitochondria-related factors, such as BCL2 family members, the apoptosome components, the autophagy/death cross-talkers and molecules regulating mitochondrial structure and functions. Turning the double-edged swords of death molecules into plougshares may turn out to be strategically crucial in molecular oncology
MIR7–3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1
Full text linkMacroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and Beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC. Of note, post-transcriptional regulation mediated by noncoding microRNAs (MIRNAs) contributes significantly to control autophagy. Here we describe a new role for the microRNA MIR7-3HG/MIR-7 as a potent autophagy inhibitor. Indeed, MIR7-3HG targets the 30 untranslated region (UTR) of AMBRA1 mRNA, inducing a decrease of both AMBRA1 mRNA and protein levels, and thus causing a block in autophagy. Furthermore, MIR7-3HG, through AMBRA1 downregulation, prevents MYC dephosphorylation, establishing a positive feedback for its own transcription. These data suggest a new and interesting role of MIR7-3HG as an anti-autophagic MIRNA that may affect oncogenesis through the regulation of the tumor suppressor AMBRA1
Apoptosome structure and regulation
No full textThe apoptosome is a multimolecular complex assembled around the adaptor protein Apaf I upon mitochondria-mediated apoptosis. The formation of the apoptosome needs the presence of ATP/dATP and cytochrome c in the cytosol and triggers the activation of caspases which - in turn - drive cell demise. Apoptosis plays a key role in the homeostasis of all multicellular organisms and, indeed, with regard to its essential components the apoptosome is evolutionary conserved. However, higher eukaryotes, according to their complexity, have evolved more complicated and finely tuned mechanisms for controlling apoptosome activity. Since apoptosome dysfunctions can cause many human diseases, this complex is also a relevant molecular target in biomedicine and the understanding of its structure and its regulation is matter of great interest for scientists
Mitochondrial dismissal in mammals, from protein degradation to mitophagy
No full textMitochondria are double-membraned highly dynamic organelles; the shape, location and function of which are determined by a constant balance between opposing fusion and fission events. A fine modulation of mitochondrial structure is crucial for their correct functionality and for many physiological cell processes, the status of these organelles, being thus a key aspect in a cell's fate. Indeed, the homeostasis of mitochondria needs to be highly regulated for the above mentioned reasons, and since a) they are the major source of energy; b) they participate in various signaling pathways; albeit at the same time c) they are also the major source of reactive oxygen species (ROS, the main damaging detrimental players for all cell components). Elaborate mechanisms of mitochondrial quality control have evolved for maintaining a functional mitochondrial network and avoiding cell damage. The first mechanism is the removal of damaged mitochondrial proteins within the organelle via chaperones and protease; the second is the cytosolic ubiquitin–proteasome system (UPS), able to eliminate proteins embedded in the outer mitochondrial membrane; the third is the removal of the entire mitochondria through mitophagy, in the case of extensive organelle damage and dysfunction. In this review, we provide an overview of these mitochondria stability and quality control mechanisms, highlighting mitophagy, and emphasizing the central role of mitochondrial dynamics in this context. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components
Apotosome: structure and regulation
No full textThe apoptosome is a multimolecular complex assembled around the adaptor protein Apaf1 upon mitochondria-mediated apoptosis. The formation of the apoptosome needs the presence of ATP/dATP and cytochrome c in the cytosol and triggers the activation of caspases which - in turn - drive cell demise. Apoptosis plays a key role in the homeostasis of all multicellular organisms and, indeed, with regard to its essential components the apoptosome is evolutionary conserved. However, higher eukaryotes, according to their complexity, have evolved more complicated and finely tuned mechanisms for controlling apoptosome activity. Since apoptosome dysfunctions can cause many human diseases, this complex is also a relevant molecular target in biomedicine and the understanding of its structure and its regulation is matter of great interest for scientists
HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy
Full text linkReceptor-mediated mitophagy is a crucial process involved in mitochondria quality control. AMBRA1 is a mitophagy receptor for the selective removal of damaged mitochondria in mammalian cells. A critical unresolved issue is how AMBRA1-mediated mitophagy is controlled in response to cellular stress. Here, we investigated the role of BCL2-family proteins on AMBRA1-dependent mitophagy and showed that MCL1 delays AMBRA1-dependent mitophagy. Indeed, MCL1 overexpression is sufficient to inhibit recruitment to mitochondria of the E3 Ubiquitin ligase HUWE1, a crucial dynamic partner of AMBRA1, upon AMBRA1-mediated mitophagy induction. In addition, we found that during mitophagy induced by AMBRA1, MCL1 levels decreased but were sustained by inhibition of the GSK-3β kinase, which delayed AMBRA1-mediated mitophagy. Also, we showed that MCL1 was phosphorylated by GSK-3β at a conserved GSK-3 phosphorylation site (S159) during AMBRA1-mediated mitophagy and that this event was accompanied by HUWE1-dependent MCL1 degradation. Altogether, our results demonstrate that MCL1 stability is regulated by the kinase GSK-3β and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy. Our work thus defines MCL1 as an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Ambra1 at a glance
No full textThe activating molecule in Beclin-1-regulated autophagy (Ambra1), also known as autophagy/Beclin-1 regulator 1, is a highly intrinsically disordered and vertebrate-conserved adapter protein that is part of the autophagy signaling network. It acts in an early step of mammalian target of rapamycin complex 1 (mTORC1)-dependent autophagy by favouring formation of the autophagosome core complex. However, recent studies have revealed that Ambra1 can also coordinate a cell response upon starvation or other stresses that involve translocation of the autophagosome core complex to the endoplasmic reticulum (ER), regulative ubiquitylation and stabilization of the kinase ULK1, selective mitochondria removal and cell cycle downregulation. Moreover, Ambra1 itself appears to be targeted by a number of regulatory processes, such as cullin-dependent degradation, caspase cleavage and several modifications, ranging from phosphorylation to ubiquitylation. Altogether, this complex network of regulation highlights the importance of Ambra1 in crucial physiological events, including metabolism, cell death and cell division. In addition, Ambra1 is an important regulator of embryonic development, and its mutation or inactivation has been shown to correlatewith several pathologies of the nervous system and to be involved in carcinogenesis. In this Cell Science at a Glance article and the accompanying poster, we discuss recent advances in the Ambra1 field, particularly the role of this proautophagic protein in cellular pathophysiology
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