Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate in Drosophila larvae

ABSTRACTThe Drosophila bang-sensitive mutant tko25t, manifesting a global deficiency in oxidative phosphorylation due to a mitochondrial protein synthesis defect, exhibits a pronounced delay in larval development. We previously identified a number of metabolic abnormalities in tko25t larvae, including elevated pyruvate and lactate, and found the larval gut to be a crucial tissue for the regulation of larval growth in the mutant. Here we established that expression of wild-type tko in any of several other tissues of tko25t also partially alleviates developmental delay. The effects appeared to be additive, whilst knockdown of tko in a variety of specific tissues phenocopied tko25t, producing developmental delay and bang-sensitivity. These findings imply the existence of a systemic signal regulating growth in response to mitochondrial dysfunction. Drugs and RNAi-targeted on pyruvate metabolism interacted with tko25t in ways that implicated pyruvate or one of its metabolic derivatives in playing a central role in generating such a signal. RNA-seq revealed that dietary pyruvate-induced changes in transcript representation were mostly non-coherent with those produced by tko25t or high-sugar, consistent with the idea that growth regulation operates primarily at the translational and/or metabolic level.Peer reviewe

Effects on Dopaminergic Neurons Are Secondary in COX-Deficient Locomotor Dysfunction in Drosophila

Dopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases. Here we investigated a Drosophila model of locomotor disorders in which functional impairment is brought about by pan-neuronal RNAi knockdown of subunit COX7A of cytochrome oxidase (COX). Despite minimal neuronal loss by apoptosis, the expression and activity of tyrosine hydroxylase was decreased by half. Surprisingly, COX7A knockdown specifically targeted to DA neurons did not produce locomotor defect. Instead, using various drivers, we found that COX7A knockdown in specific groups of cholinergic and glutamatergic neurons underlay the phenotype. Based on our main finding, the vulnerability of DA neurons to mitochondrial dysfunction as a cause of impaired locomotion in other organisms, including mammals, warrants detailed investigation.Peer reviewe

Diiron centre mutations in Ciona intestinalis alternative oxidase abolish enzymatic activity and prevent rescue of cytochrome oxidase deficiency in flies

The mitochondrial alternative oxidase, AOX, carries out the non proton-motive re-oxidation of ubiquinol by oxygen in lower eukaryotes, plants and some animals. Here we created a modified version of AOX from Ciona instestinalis, carrying mutations at conserved residues predicted to be required for chelation of the diiron prosthetic group. The modified protein was stably expressed in mammalian cells or flies, but lacked enzymatic activity and was unable to rescue the phenotypes of flies knocked down for a subunit of cytochrome oxidase. The mutated AOX transgene is thus a potentially useful tool in studies of the physiological effects of AOX expression.Peer reviewe

New Alien Mediterranean Biodiversity Records (October 2020)

This article includes 23 new records of alien and cryptogenic species in the Mediterranean Sea, belonging to 4 Phyla (Chordata, Echinodermata, Arthropoda and Mollusca), distributed from the Alboran to the Levantine Sea. Records are reported from eight countries listed from West to East as follows: Algeria: new records of the Atlantic blue crab Callinectes sapidus; Spain: further spread and establishment of the sea slug Lamprohaminoea ovalis in continental shores; Tunisia: first record of the Atlantic Blue Crab Callinectes sapidus in the Gulf of Gabes; Italy: a new occurrence of the pufferfish Lagocephalus sceleratus in Northern Ionian waters; first record of Cephalopholis taeniops in the Ionian Sea; first record of the redlip blenny, Ophioblennius atlanticus in the Ionian Sea; Slovenia: first record of the isopod Paranthura japonica in Slovenia; Greece: first record of the molluscs Eunaticina papilla, Plocamopherus ocellatus and the fish Cheilodipterus novemstriatus; first record of the ascidian Ecteinascidia turbinata in Kriti; the long-spined sea urchin Diadema setosum in the Ionian Sea; Turkey: first record of the sea spider Ammothea hilgendorfi; the stomatopod Cloridina cf. ichneumon; the fishes Pempheris rhomboidea from the Sea of Marmara and Paranthias furcifer from the Aegean Sea; Lebanon: new records of the fishes Arothron hispidus, Rachycentron canadum, Heniochus intermedius and Acanthurus monroviae; first record of Acanthostracion polygonius. The records of Cloridina cf. ichneumon from southern Turkey and the fish Acanthostracion polygonius from Lebanon, both being the first Mediterranean records, are noteworthy

Microtubules originate asymmetrically at the somatic golgi and are guided via Kinesin2 to maintain polarity within neurons

Neurons contain polarised microtubule arrays essential for neuronal function. How microtubule nucleation and polarity are regulated within neurons remains unclear. We show that γ-tubulin localises asymmetrically to the somatic Golgi within Drosophila neurons. Microtubules originate from the Golgi with an initial growth preference towards the axon. Their growing plus ends also turn towards and into the axon, adding to the plus-end-out microtubule pool. Any plus ends that reach a dendrite, however, do not readily enter, maintaining minus-end-out polarity. Both turning towards the axon and exclusion from dendrites depend on Kinesin-2, a plus-end-associated motor that guides growing plus ends along adjacent microtubules. We propose that Kinesin-2 engages with a polarised microtubule network within the soma to guide growing microtubules towards the axon; while at dendrite entry sites engagement with microtubules of opposite polarity generates a backward stalling force that prevents entry into dendrites and thus maintains minus-end-out polarity within proximal dendrites

Toward eco-compatible synthesis of biosourced derivatives quinoline in continuous flow

Les composés incorporant un motif quinoléine occupent une place privilégiée parmi les substances pharmaceutiques, et possèdent également une large variété d’applications dans des domaines comme la cosmétique ou l’agro-alimentaire. Cependant, malgré l’intérêt de ces dérivés hétérocycliques, les synthèses classiques de quinoléines décrites dans la littérature sont peu respectueuses de l’environnement. Pour pallier à ce problème, nous avons envisagé une approche éco-compatibles usant de matières premières bio-sourcées qui serait applicable à l’échelle industrielle. Plus particulièrement, ce projet présente deux enjeux majeurs : 1) effectuer la synthèse de dérivés de quinoléine à partir de matières premières issues de la biomasse tout en respectant les principes de la chimie vertes, et 2) adapter ce procédé en flux continu, en vue d’une potentielle application industrielle. Au cours de ce travail, nous rapportons notre étude sur la transposition de la réaction de Skraup en flux continu. En particulier, nous avons développé une synthèse de quinoléines en flux continu valorisant le glycérol – sous-produit principal de la réaction de transestérification des triglycérides – comme précurseur d’acroléine, et ayant lieu dans l’eau. Ces travaux de thèse permettent de franchir une étape vers la production éco-compatibles de composés hétérocycliques.The quinoline motif is present in numerous pharmaceutically relevant drugs as well as in a wide range of active ingredients used in cosmetic and food-processing industries. Despite its prevalence, typical quinoline synthesis reported in the literature are not scalable, and do not involve green protocols that take advantage of renewable resources. To address both limitations, we envisioned a green and industrially applicable approach using abundant resources. Specifically, we faced two main challenges: 1) to develop a sustainable synthesis of quinolines and 2) to apply this synthesis in a flow apparatus for potential industrial application. Throughout this dissertation, we disclose our studies toward the sustainable Skraup reaction. In particular, we developed a flow-synthesis of quinolines proceeding from glycerol - the main byproduct of biofuel production - as a building block and water as a green solvent. This innovative method marks a step toward the green production of heterocyclic compounds