IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.

Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance.

Mical modulates Tau toxicity via cysteine oxidation in vivo.

Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains.

Amyloid toxicity in a Drosophila Alzheimer's model is ameliorated by autophagy activation.

Alzheimer's disease (AD) is the prevailing form of dementia. Protein degradation and antioxidant pathways have a critical role in preventing the accumulation of protein aggregation; thus, failure of proteostasis in neurons along with redox imbalance mark AD. Herein, we exploited an AD Drosophila model expressing human amyloid precursor (hAPP) and beta-secretase 1 (hBACE1) proteins, to better understand the role of proteostatic or antioxidant pathways in AD.

The Two Cysteines of Tau Protein Are Functionally Distinct and Contribute Differentially to Its Pathogenicity .

Although Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies, the mechanism that initiates the aggregation of this highly soluble protein remains largely unanswered. Interestingly, Tau can be induced to form fibrillar filaments by oxidation of its two cysteine residues, generating an intermolecular disulfide bond that promotes dimerization and fibrillization. The recently solved structures of Tau filaments revealed that the two cysteine residues are not structurally equivalent since Cys-322 is incorporated into the core of the fibril, whereas Cys-291 projects away from the core to form the fuzzy coat.

Alterations in Organismal Physiology, Impaired Stress Resistance, and Accelerated Aging in Flies Adapted to Multigenerational Proteome Instability.

Being an assembly of highly sophisticated protein machines, cells depend heavily on proteostatic modules functionality and on adequate supply of energetic molecules for maintaining proteome stability. Yet, our understanding of the adaptations induced by multigenerational proteotoxic stress is limited. We report here that multigenerational (>80 generations) proteotoxic stress in Oregon flies induced by constant exposure to developmentally nonlethal doses of the proteasome inhibitor bortezomib (BTZ) ( flies) increased proteome instability and redox imbalance, reduced fecundity and body size, and caused neuromuscular defects; it also accelerated aging.

Functional wiring of proteostatic and mitostatic modules ensures transient organismal survival during imbalanced mitochondrial dynamics.

Being an assembly of protein machines, cells depend on adequate supply of energetic molecules for retaining their homeodynamics. Consequently, mitochondria functionality is ensured by quality control systems and mitochondrial dynamics (fusion/fission). Similarly, proteome stability is maintained by the machineries of the proteostasis network.

Proteasome dysfunction induces excessive proteome instability and loss of mitostasis that can be mitigated by enhancing mitochondrial fusion or autophagy.

The ubiquitin-proteasome pathway (UPP) is central to proteostasis network (PN) functionality and proteome quality control. Yet, the functional implication of the UPP in tissue homeodynamics at the whole organism level and its potential cross-talk with other proteostatic or mitostatic modules are not well understood. We show here that knock down (KD) of proteasome subunits in flies, induced, for most subunits, developmental lethality.

Comparison survey of EVOO polyphenols and exploration of healthy aging-promoting properties of oleocanthal and oleacein.

Olive oil is widely accepted as a superior edible oil. Great attention has been given lately to olive oil polyphenols which are linked to significant health beneficial effects. Towards a survey of Greek olive oil focusing on polyphenols, representative extra virgin olive oils (EVOOs) from the main producing areas of the country and the same harvesting period have been collected and analyzed.

Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.

Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance.

Selective cytotoxicity of the herbal substance acteoside against tumor cells and its mechanistic insights.

Natural products are characterized by extreme structural diversity and thus they offer a unique source for the identification of novel anti-tumor agents. Herein, we report that the herbal substance acteoside being isolated by advanced phytochemical methods from Lippia citriodora leaves showed enhanced cytotoxicity against metastatic tumor cells; acted in synergy with various cytotoxic agents and it sensitized chemoresistant cancer cells. Acteoside was not toxic in physiological cellular contexts, while it increased oxidative load, affected the activity of proteostatic modules and suppressed matrix metalloproteinases in tumor cell lines.

Milder degenerative effects of Carfilzomib vs. Bortezomib in the Drosophila model: a link to clinical adverse events.

Proteasome inhibitors, e.g. Bortezomib (BTZ) and Carfilzomib (CFZ), have demonstrated clinical efficacy against haematological cancers.

Isolation of natural products with anti-ageing activity from the fruits of Platanus orientalis.

Background: Ageing is defined as the time-dependent decline of functional capacity and stress resistance resulting in increased morbidity and mortality.

Hypothesis/purpose: Reportedly, these effects can be delayed by mild genetic or pharmacological activation of the main modules of the proteostasis network.

Study Design-methods: By employing advanced phytochemical methods we isolated natural products from the fruits of Platanus orientalis and studied (via a bio-guided approach) their effects in Drosophila flies, as well as in normal human fibroblasts.

The Indirubin Derivative 6-Bromoindirubin-3'-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects.

Aims: Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrient-sensing pathway signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform, we searched for compounds that modulate these pathways.

Results: We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy life span. 6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, decreased lipid and glucose tissue load, activated antioxidant and proteostatic modules, and enhanced resistance to stressors.

The amazing ubiquitin-proteasome system: structural components and implication in aging.

Proteome quality control (PQC) is critical for the maintenance of cellular functionality and it is assured by the curating activity of the proteostasis network (PN). PN is constituted of several complex protein machines that under conditions of proteome instability aim to, firstly identify, and then, either rescue or degrade nonnative polypeptides. Central to the PN functionality is the ubiquitin-proteasome system (UPS) which is composed from the ubiquitin-conjugating enzymes and the proteasome; the latter is a sophisticated multi-subunit molecular machine that functions in a bimodal way as it degrades both short-lived ubiquitinated normal proteins and nonfunctional polypeptides.

Diet-derived advanced glycation end products or lipofuscin disrupts proteostasis and reduces life span in Drosophila melanogaster.

Advanced glycation end product (AGE)-modified proteins are formed by the nonenzymatic glycation of free amino groups of proteins and, along with lipofuscin (a highly oxidized aggregate of covalently cross-linked proteins, sugars, and lipids), have been found to accumulate during aging and in several age-related diseases. As the in vivo effects of diet-derived AGEs or lipofuscin remain elusive, we sought to study the impact of oral administration of glucose-, fructose-, or ribose-modified albumin or of artificial lipofuscin in a genetically tractable model organism. We report herein that continuous feeding of young Drosophila flies with culture medium enriched in AGEs or in lipofuscin resulted in reduced locomotor performance and in accelerated rates of AGE-modified proteins and carbonylated proteins accumulation in the somatic tissues and hemolymph of flies, as well as in a significant reduction of flies health span and life span.

Proteasome dysfunction in Drosophila signals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging.

The ubiquitin-proteasome system is central to the regulation of cellular proteostasis. Nevertheless, the impact of in vivo proteasome dysfunction on the proteostasis networks and the aging processes remains poorly understood. We found that RNAi-mediated knockdown of 20S proteasome subunits in Drosophila melanogaster resulted in larval lethality.

Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress.

Proteasome is central to proteostasis maintenance, as it degrades both normal and damaged proteins. Herein, we undertook a detailed analysis of proteasome regulation in the in vivo setting of Drosophila melanogaster. We report that a major hallmark of somatic tissues of aging flies is the gradual accumulation of ubiquitinated and carbonylated proteins; these effects correlated with a ~50% reduction of proteasome expression and catalytic activities.