Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in
cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that ...MFN2 activity can be determined by Met
and His
interactions with Asp
and Leu
and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser
Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg
→Gln
and MFN2 Thr
→Met
, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr
→Met
mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.
BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF
signals as an active monomer in the absence of active RAS, however, in many tumors ...BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.
Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational ...changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
Recent advances highlight the role of mitochondrial dynamics proteins and mitochondrial fusion/fission in cell physiology and diverse human pathologies.Significant progress in structural and ...biochemical investigations has illuminated the molecular mechanisms of mitochondrial fusion and fission that will inform rational strategies for drug targeting.Small molecules targeting mitochondrial dynamics proteins have demonstrated promising pharmacological activity and highlight the druggability of these proteins.Pharmacological restoration of deregulated mitochondrial dynamics decreased the progression of various pathologies.
The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure–function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
The crosstalk between mitochondria and the nucleus regulates cell plasticity and innate immune response. A new study shows that copper(II) accumulates in mitochondria of activated macrophages in ...response to pathogen infection and induces metabolic and epigenetic reprogramming that promotes inflammation. Pharmacologic targeting of mitochondrial copper(II) uncovers a new therapeutic strategy to combat aberrant inflammation and regulate cell plasticity.
Dynamic protein complexes function in all cellular processes, from signaling to transcription, using distinct conformations that regulate their activity. Conformational switching of proteins can turn ...on or off their activity through protein–protein interactions, catalytic function, cellular localization, or membrane interaction. Recent advances in structural, computational, and chemical methodologies have enabled the discovery of small-molecule activators and inhibitors of conformationally dynamic proteins by using a more rational design than a serendipitous screening approach. Here, we discuss such recent examples, focusing on the mechanism of protein conformational switching and its regulation by small molecules. We emphasize the rational approaches to control protein oligomerization with small molecules that offer exciting opportunities for investigation of novel biological mechanisms and drug discovery.
Small molecules can control protein oligomerization by stabilizing or promoting a particular conformational state.Small molecules that turn on and off conformational changes provided important insights into protein function and biological mechanisms.Αdvances in several methodologies enabled the discovery of small-molecule activators and inhibitors of protein conformational changes.A structure-guided drug discovery platform for targeting conformational plasticity of proteins with small-molecule modulators will accelerate the discovery of novel chemical probes and drug candidates in diverse biological mechanisms.
Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells' (bCSCs) response to RS ...and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
Energy efficiency tools for residential users Zacharioudakis, Emmanouil; Leligou, Helen C.; Papadopoulou, Aikaterini
MATEC Web of Conferences,
01/2017, Letnik:
125
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Residential energy consumption reserves a significant portion of the total energy consumption in modern cities. The rates of construction of new buildings as well as the rates of renovation on ...existing ones are generally very low. At the same time, unlike centrally operated large commercial buildings, the installation of energy management systems is a rather expensive solution leaving residential users with limited means to improve their energy efficiency as results are not evident. Considering that to drive energy efficient behaviour, we have to first raise awareness, then provide evidence through measurements and then support further, more elaborate, energy efficiency actions, we capitalise on ICT as soft measures towards reaching hard goals. We propose a novel incremental solution starting from a rather simple mobile application exploiting the sensors available in our smartphones and tablets to proceed to more intelligent advice provisioning towards energy efficiency. We present its implementation architecture and discuss certain market-wise challenges to prove its potential.
Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)
. Mitochondria are major regulators of the SASP; ...however, the underlying mechanisms have not been elucidated
. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die
. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
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