1,721,681 research outputs found
Dying to survive - Apoptosis, necroptosis, autophagy as the supreme experiments of nature
No full textGuido Kroemer has made fundamental contributions to medical research through his pioneering work in the fields of cell death and cancer research. He is best known for the discovery that the permeabilization of mitochondrial membranes constitutes a decisive step in programmed cell death. Kroemer has explored the fine mechanisms of mitochondrial cell death control, the molecular pathways that explain the inhibition of cell death in cancer cells, upstream of or at the level of mitochondria, and the mechanisms that make cancer cell death immunogenic. Moreover, he discovered the AIF protein and clarified its biological role in apoptosis. His important contributions have been recognized with numerous awards. Kroemer currently serves on more than forty Editorial Boards and is a member of the European Molecular Biology Organization (EMBO), German Academy of Sciences, Austrian Academy of Sciences, European Academy of Sciences (EAS), European Academy of Sciences and Arts (EASA), and European Academy of Cancer Sciences (EACS). He is the President of the European Cell Death Organization (ECDO) and the Founding Director of the European Research Institute for Integrated Cellular Pathology (ERI-ICP). Kroemer is the most cited scientist worldwide in the field of cell death as well as in the area of mitochondrial research
Therapeutic modulation of autophagy: which disease comes first?
No full textThe relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy “druggable”. Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation
Altering mitochondrial properties
No full textThe mitochondrial permeability transition pore (mPTP) is a multiprotein complex that regulates cell death in multiple pathological conditions. The discovery of new critical components of the mPTP and the identification of anticancer drugs acting on mPTP opens new frontiers for mitochondrial medicine
GD3 ganglioside directly targets mitochondria and induces the release of apoptogenic factors
Full text linkLipid and glycolipid diffusible mediators
are involved in the intracellular progression and
amplification of apoptotic signals. GD3 ganglioside
is rapidly synthesized from accumulated ceramide
after the clustering of death-inducing receptors and
triggers apoptosis. Here we show that GD3 induces
dissipation of DCm and swelling of isolated mitochondria,
which results in the mitochondrial release
of cytochrome c, apoptosis inducing factor, and
caspase 9. Soluble factors released from GD3-
treated mitochondria are sufficient to trigger DNA
fragmentation in isolated nuclei. All these effects can
be blocked by cyclosporin A, suggesting that GD3 is
acting at the level of the permeability transition pore
complex. We found that endogenous GD3 accumulates
within mitochondria of cells undergoing apoptosis
after ceramide exposure. Accordingly, suppression
of GD3 synthase (ST8) expression in intact
cells substantially prevents ceramide-induced DCm
dissipation, indicating that endogenously synthesized
GD3 induces mitochondrial changes in vivo. Finally,
enforced expression of bcl-2 significantly prevents
GD3-induced mitochondrial changes, caspase 9 activation,
and apoptosis. These results show that mitochondria
are a key destination for apoptogenic GD3
ganglioside along the lipid pathway to programmed
cell death and indicate that relevant GD3 targets are
under bcl-2 control.—Rippo, M. R., Malisan, F.,
Ravagnan, L., Tomassini, B., Condo, I., Costantini,
P., Susin, S. A., Rufini, A., Todaro, M., Kroemer, G.,
Testi, R. GD3 ganglioside directly targets mitochondria
in a bcl-2-controlled fashion
Apoptosis-inducing factor (AIF): Key to the conserved caspase-independent pathways of cell death?
No full textNumerous pro-apoptotic signal transducing molecules act on mitochondria and provoke the permeabilization of the outer mitochondrial membrane, thereby triggering the release of potentially toxic mitochondrial proteins. One of these proteins, apoptosis-inducing factor (AIF), is a phylogenetically old flavoprotein which, in healthy cells, is confined to the mitochondrial intermembrane space. Upon lethal signaling, AIF translocates, via the cytosol, to the nucleus where it binds to DNA and provokes caspase-independent chromatin condensation. The crystal structures of both human and mouse AIF have been determined, and the fine mechanisms accounting for its oxidoreductase activity and its electrostatic interaction with double-stranded DNA have been elucidated. Importantly, the apoptogenic and oxidoreductase functions of AIF can be dissociated. Thus, mutations that abolish the AIF-DNA interaction suppress AIF-induced chromatin condensation, yet have no effect on the NADH oxidase activity. Recent studies suggest AIF to be a major factor determining caspase-independent neuronal death, emphasizing the central role of mitochondria in the control of physiological and pathological cell demise
Mitotic catastrophe: a mechanism for avoiding genomic instability
No full textThe improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint
Coronavirus infections: epidemiological, clinical and immunological features and hypotheses
Full text linkCoronaviruses (CoVs) are a large family of enveloped, positivestrand RNA viruses. Four human CoVs (HCoVs), the non-severe acute respiratory syndrome (SARS)-like HCoVs (namely HCoV 229E, NL63, OC43, and HKU1), are globally endemic and account for a substantial fraction of upper respiratory tract infections. Non-SARS-like CoV can occasionally produce severe diseases in frail subjects but do not cause any major (fatal) epidemics. In contrast, SARS like CoVs (namely SARS-CoV and Middle-East respiratory syndrome coronavirus, MERS-CoV) can cause intense short-lived fatal outbreaks. The current epidemic caused by the highly contagious SARS-CoV-2 and its rapid spread globally is of major concern. There is scanty knowledge on the actual pandemic potential of this new SARS-like virus. It might be speculated that SARS-CoV-2 epidemic is grossly underdiagnosed and that the infection is silently spreading across the globe with two consequences: (i) clusters of severe infections among frail subjects could haphazardly occur linked to unrecognized index cases; (ii) the current epidemic could naturally fall into a low-level endemic phase when a significant number of subjects will have developed immunity. Understanding the role of paucisymptomatic subjects and stratifying patients according to the risk of developing severe clinical presentations is pivotal for implementing reasonable measures to contain the infection and to reduce its mortality. Whilst the future evolution of this epidemic remains unpredictable, classic public health strategies must follow rational patterns. The emergence of yet another global epidemic underscores the permanent challenges that infectious diseases pose and underscores the need for global cooperation and preparedness, even during inter-epidemic periods
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