A Connection between the Mitochondrial Permeability Transition Pore, Autophagy, and Cerebral Amyloidogenesis

Šoškić, Vukic; Klemm, Martina; Proikas‐Cezanne, Tassula; Schwall, Gerhard P.; Poznanović, Slobodan; Stegmann, Werner; Groebe, Karlfried; Zengerling, Helmut; Schoepf, Rainer; Burnet, Michael; Schrattenholz, André

doi:10.1021/pr700686x

Cited by 15 publications

(16 citation statements)

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“…86 There are also a small number of reports correlating the MPTP with autophagy. [87][88][89][90] Additionally, mitochondrial Ca 2+ release after membrane potential collapse could activate autophagy as a result of increased cytosolic Ca 2+ . 91 With the ability of mitochondria to sequester cytosolic Ca 2+ and in doing so regulate the onset of autophagy, one could hypothesize that mitochondrial Ca 2+ may influence the elimination of dysfunctional mitochondria.…”

Section: Camentioning

confidence: 99%

Ca²⁺in quality control

East

Campanella

2013

Autophagy

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Section: Camentioning

confidence: 99%

Ca²⁺in quality control

East

Campanella

2013

Autophagy

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“…The reality of current pharmaceuticals out in the market, however, includes a significant segment of successful drugs which have low selectivities and affinities and multiple targets (24) where the exact modes of action are far from clear. Given, for example, the complex and polyetiological molecular biological background of central nervous system disorders, functional genomic and in particular proteomic profiling of efficacy models (25,26) increasingly contribute to drug development (27)(28)(29)(30). The enormous functional flexibility of many protein targets results in crosstalk and pleiotropy, generating combinatorial effects and cascades of non-linear cellular functions.…”

Section: Genetic Interaction Network Analysismentioning

confidence: 99%

“…"Chemical proteomics," is employing active site-directed chemical affinity probes to explore "interacting proteomes" for drugs/ligands as a special embodiment of affinity fractionation (30,116) (Fig. 4).…”

Section: Chemical Proteomicsmentioning

confidence: 99%

“…To date, this type of technology has been used successfully to target all major classes of proteases, kinases, phosphatases, glycosidases, GSTs, oxidoreductases, phosphatidyl-inositol 3-kinase signalling and histone deacetylases as well as for post-translationally modified proteins (24,(117)(118)(119). Bulky reporter tags, such as fluorophores or biotin, can be replaced with much smaller azide or alkyne groups which enable profiling of enzyme activities in living cells and animals (30,120). In these experiments, post-labelling Fig.…”

Section: Chemical Proteomicsmentioning

confidence: 99%

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Systems Biology Approaches and Tools for Analysis of Interactomes and Multi-target Drugs

Schrattenholz

Groebe²,

Šoškić³

2010

Methods in Molecular Biology

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Systems biology is essentially a proteomic and epigenetic exercise because the relatively condensed information of genomes unfolds on the level of proteins. The flexibility of cellular architectures is not only mediated by a dazzling number of proteinaceous species but moreover by the kinetics of their molecular changes: The time scales of posttranslational modifications range from milliseconds to years. The genetic framework of an organism only provides the blue print of protein embodiments which are constantly shaped by external input. Indeed, posttranslational modifications of proteins represent the scope and velocity of these inputs and fulfil the requirements of integration of external spatiotemporal signal transduction inside an organism. The optimization of biochemical networks for this type of information processing and storage results in chemically extremely fine tuned molecular entities. The huge dynamic range of concentrations, the chemical diversity and the necessity of synchronisation of complex protein expression patterns pose the major challenge of systemic analysis of biological models. One further message is that many of the key reactions in living systems are essentially based on interactions of moderate affinities and moderate selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. In complex disorders such as cancer or neurodegenerative diseases, which initially appear to be rooted in relatively subtle dysfunctions of multimodal physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which has been dominating the pharmaceutical industry for a long time, increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade, and the treatment of "complex diseases" remains a most pressing medical need. Currently, a change of paradigm can be observed with regard to a new interest in agents that modulate multiple targets simultaneously, essentially "dirty drugs." Targeting cellular function as a system rather than on the level of the single target, significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data. But the key is the extraction of relevant molecular information from biological systems by implementing rigid statistical procedures to differential proteomic analytics.

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“…2 and 6) we analyzed whether the impairment of autophagy observed in absence of TG2 could determine the accumulation of undigested mitochondrial proteins in the cytoplasm, as recently reported. 31 Data antibodies were from Jackson Immunoresearch Labs. Earle's balanced salt solution (EBSS) (E2888), rapamycin (R0395), 2-deoxy-D-glucose (D6134), bafilomycin A1 (B1793), NH 4 Cl (A0171) and acridine orange (A8097) were obtained from Sigma.…”

mentioning

confidence: 99%