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Farmed salmon escape and interbreed with wild Atlantic salmon on a large scale. We studied introgression of mitochondrial haplotypes from farmed Atlantic salmon originating from the Eastern Atlantic phylogenetic group to wild salmon of the Barents-White Sea (BWS) phylogenetic group. We find that farmed genetic introgression introduced novel, non-native haplotypes into the BWS phylogenetic group. The mitochondrial genome has important functional effects and is inherited as a haploid from the mother. Hence, the observed introgression across natural genetic barriers is expected to cause long- lasting functional maladaptation of the hybrids in the maternal line. As the use of farmed Atlantic salmon from non-native phylogenetic groups is widespread in aquaculture, the impact on wild Atlantic salmon may be more severe than previously recognized. Our results highlight the ecological risks of releasing non-native wild and domesticated animals. Key words: Atlantic salmon, aquaculture, genetic introgression, Salmo salar, phylogeny, haplotypes, Introduction Human-mediated gene flow is widespread and has detrimental effects on wild populations (Crispo et al. 2011; Ottenburghs 2021). Important and growing causes of human-mediated gene flow are escaped domesticated [...]

Understanding the spatial scale of population processes is critical for contextualizing monitoring and prioritizing conservation actions. Green turtle (Chelonia mydas) abundance in the Greater Caribbean (GC) region is rebounding from centuries of overexploitation, but recovery trajectories vary among nesting populations. Maternally inherited mitochondrial DNA control region (CR) markers can link juveniles to their source populations, providing spatial ecology context for interpreting differential population trends. However, CR haplotype CM-A3 is shared across all western GC sites, limiting resolution. In this study, 387 females from Tortuguero, Costa Rica, the largest nesting population in the western Atlantic, were reanalyzed through sequencing of an expanded (817-base pair) CR fragment and the mitochondrial short tandem repeat (mtSTR) array. Variation in mtSTR sequences yielded 12 Tortuguero CM-A3 haplotypes. No structure was detected in mtSTR haplotype frequencies spatially or temporally within the Tortuguero rookery. In GC regional comparisons, Tortuguero CM-A3 mtSTR haplotype frequencies were significantly different from those of published Cayman Islands and major Florida nesting populations. This improved resolution of genetic structure reinforces the inference of demographic discreteness of these nesting populations with respect to female natal homing. Furthermore, these refinements provide critical baseline data to reduce uncertainty in future mixed stock analyses. The mtSTR may prove useful in resolving stock structure and migratory connectivity in green turtles in other regions where common CR haplotypes are broadly distributed., Author(s): Brian M. Shamblin [sup.1] , Alan B. Bolten [sup.2] , Karen A. Bjorndal [sup.2] Author Affiliations: (1) grid.213876.9, 0000 0004 1936 738X, Warnell School of Forestry and Natural Resources, [...]

In the kidney, the accumulation of heavy metals such as [Cd.sup.2+] produces mitochondrial dysfunctions, i.e., uncoupling of the oxidative phosphorylation, inhibition of the electron transport through the respiratory chain, and collapse of the transmembrane electrical gradient. This derangement may be due to the fact that [Cd.sup.2+] induces the transition of membrane permeability from selective to nonselective via the opening of a transmembrane pore. In fact, [Cd.sup.2+] produces this injury through the stimulation of oxygen-derived radical generation, inducing oxidative stress. Several molecules have been used to avoid or even reverse [Cd.sup.2+]-induced mitochondrial injury, for instance, cyclosporin A, resveratrol, dithiocarbamates, and even EDTA The aim of this study was to explore the possibility that the antioxidant tamoxifen could protect mitochondria from the deleterious effects of [Cd.sup.2+]. Our results indicate that the addition of 1 [micro]mol/L [Cd.sup.2+] to mitochondria collapsed the transmembrane electrical gradient, induced the release of cytochrome c, and increased both the generation of [H.sub.2][O.sub.2] and the oxidative damage to mitochondrial DNA (among other measured parameters). Of interest, these mitochondrial dysfunctions were ameliorated after the addition of tamoxifen. Key words: mitochondria, kidney, cadmium, oxidative stress, permeability transition. Dans le rein, l'accumulation de metaux lourds comme le [Cd.sup.2+] provoque des dysfonctionnements mitochondriaux c'est-a-dire le decouplage de la phosphorylation oxydative, l'inhibition du transport des electrons a travers la chaine respiratoire et l'effondrement de gradient electrique transmembranaire. Ce dereglement peut etre du au fait que le [Cd.sup.2+] induit la transition de la permeabilite membranaire d'un etat selectif a un etat non selectif au moyen de l'ouverture des pores transmembranaires. En fait, le [Cd.sup.2+] produit ce dommage par la stimulation de la generation de radicaux libres d'oxygene menant a un stress oxydant. Plusieurs molecules ont ete utilisees pour eviter ou meme renverser le dommage aux mitochondries induit par le [Cd.sup.2+], par exemple, la cyclosporine A, le resveratrol, les dithiocarbamates et meme l'EDTA. L'objectif de la presente etude etait d'explorer la possibilite que le tamoxifene, un antioxydant, puisse preserver la fonction mitochondriale des effets nocifs du [Cd.sup.2+]. Les resultats des auteurs indiquent que l'ajout de 1 [micro]mol/L de [Cd.sup.2+] a des mitochondries provoquait l'effondrement du gradient electrique transmembranaire, induisait la liberation de cytochrome c et augmentait la production de [H.sub.2][O.sub.2] et le dommage oxydant a l'ADN mitochondrial (parmi d'autres parametres mesures). Fait interessant, ces dysfonctionnements mitochondriaux etaient attenues a la suite de l'ajout de tamoxifene. [Traduit par la Redaction] Mots-cles: mitochondrie, rein, cadmium, stress oxydant, transition de permeabilite., Introduction Cadmium is a heavy metal pollutant derived from several industrial activities, such as the production of batteries and pigment for paint production; it is also a contaminant in cigarette [...]

Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction occurring independently of a recognized cause such as hypertension or coronary artery disease. Liver X receptor [alpha] (LXR[alpha]), a subtype of ligand-activated transcription factors LXRs, has been considered as a potential pharmacological target in the pathogenesis of cardiovascular and metabolic diseases. However, the potential mechanism of how LXR[alpha] is regulated in cardiomyocytes is still unclear. This study investigated the effect of activating LXR[alpha] with GW3965 on cardiomyocyte apoptosis and its upstream regulator in glucose-induced H9C2 cells. Our data indicated that GW3965 up-regulated the expression of LXR[alpha], inhibited cardiomyocyte apoptosis, and altered the apoptosis-related proteins in glucose-induced H9C2 cells. In addition, GW3965 restored the mitochondrial membrane potential level and decreased the ROS production induced by glucose. Moreover, LXR[alpha] was confirmed as a direct target of microRNA-1 (miR-1) that was involved in cardiomyocyte apoptosis of DCM, and overexpression of miR-1 abrogated the inhibiting effect of GW3965 on glucose-induced apoptosis in H9C2 cells. This study highlights an important role of LXR[alpha] in the development of DCM and brings new insights into the complex mechanisms involved in the pathogenesis of DCM. Key words: diabetic cardiomyopathy, liver X receptor [alpha], microRNA-1, apoptosis, reactive oxygen species. La cardiomyopathie diabétique (CMD) est définie comme un dysfonctionnement ventriculaire qui survient indépendamment d'une cause reconnue comme l'hypertension ou la coronaropathie. Le récepteur nucléaire LXR[alpha] (<>), un sous-type des facteurs de transcription activés par les ligands LXR, a été considéré comme cible pharmacologique potentielle dans la pathogenèse des maladies cardiovasculaires et métaboliques. Cependant, le possible mécanisme par lequel le LXR[alpha] est régulé dans les cardiomyocytes n'est toujours pas clair. Cette étude visait à examiner l'effet de l'activation du LXR[alpha] par le GW3965 sur l'apoptose des cardiomyocytes et sur ses régulateurs en amont chez les cellules H9C2 traitées au glucose. Les données ont révélé que le GW3965 régulait à la hausse l'expression du LXR[alpha], inhibait l'apoptose des cardiomyocytes et modifiait l'expression des protéines liées à l'apoptose chez les cellules H9C2 traitées au glucose. De plus, le GW3965 rétablissait le potentiel membranaire mitochondrial et diminuait la production de DRO induite par le glucose. En outre, puisque le LXR[alpha] s'est avéré une cible directe du microARN-1 (miR-1) impliqué dans l'apoptose des cardiomyocytes dans la CMD, la surexpression de miR-1 abolissait l'effet inhibiteur du GW3965 sur l'apoptose induite par le glucose chez les cellules H9C2. Cette étude souligne le rôle important du LXR[alpha] dans le développement de la CMD et apporte de nouvelles connaissances pour mieux comprendre les mécanismes complexes impliqués dans la pathogenèse de la CMD. [Traduit par la Rédaction] Mots-clés: cardiomyopathie diabétique, LXR [alpha], microARN-1, apoptose, dérivés réactifs de l'oxygène., Introduction There is a growing amount of data showing that patients with diabetes mellitus (DM) display a high risk of developing heart failure, independent from other risk factors such as [...]

BRCA1-associated protein 1 (BAP1) regulates calcium flux in the endoplasmic reticulum to facilitate the execution of apoptosis, unveiling a new facet of the role of BAP1 as an environmental tumour suppressor. A new role for BAP1 in tumour suppression BAP1 is a tumour suppressor associated with germline mutations in several malignancies including uveal melanoma and mesothelioma. BAP1 tumour suppressor activity has previously been linked to its nuclear role in maintaining genome integrity. Here, the authors reveal a new role for BAP1 in the endoplasmic reticulum, where it regulates calcium flux to facilitate the execution of apoptosis. Loss of BAP1 function prevents apoptosis in transformed cells with accumulated DNA damage. The results unveil a new facet of the role of BAP1 as an environmental tumour suppressor. BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis.sup.1,2,3. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1.sup.+/-) developed one and often several BAP1.sup.-/- malignancies in their lifetime.sup.4, mostly malignant mesothelioma, uveal melanoma.sup.2,5, and so on.sup.6,7,8,9,10. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers.sup.8,11,12,13,14. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity.sup.15,16,17. The possible activity of BAP1 in the cytoplasm is unknown. Cells with reduced levels of BAP1 exhibit chromosomal abnormalities and decreased DNA repair by homologous recombination.sup.18, indicating that BAP1 dosage is critical. Cells with extensive DNA damage should die and not grow into malignancies. Here we discover that BAP1 localizes at the endoplasmic reticulum. Here, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3), modulating calcium (Ca.sup.2+) release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1.sup.+/- carriers cause reduction both of IP3R3 levels and of Ca.sup.2+ flux, preventing BAP1.sup.+/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. We propose that the high incidence of cancers in BAP1.sup.+/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Our data provide a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis., Author(s): Angela Bononi [sup.1] , Carlotta Giorgi [sup.2] , Simone Patergnani [sup.2] , David Larson [sup.1] , Kaitlyn Verbruggen [sup.1] , Mika Tanji [sup.1] , Laura Pellegrini [sup.1] , Valentina [...]

Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is not completely understood. Here we show that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, we engineered a cell-permeant minipeptide to destabilize the fusion-constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbour CMT2A-associated genetic defects. The relationship between the conformational plasticity of mitofusin 2 and mitochondrial dynamism reveals a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics., Author(s): Antonietta Franco [1]; Richard N. Kitsis [2]; Julie A. Fleischer [1]; Evripidis Gavathiotis [3]; Opher S. Kornfeld [4]; Guohua Gong [1]; Nikolaos Biris [3]; Ann Benz [5]; Nir Qvit [...]

Author(s): Sara Cogliati [1]; Enrique Calvo [1]; Marta Loureiro [1]; Adela M. Guaras [1]; Rocio Nieto-Arellano [1]; Carolina Garcia-Poyatos [1, 2]; Iakes Ezkurdia [1]; Nadia Mercader [1, 2]; Jess Vzquez [...]

Oxidative phosphorylation (OXPHOS) is a vital process for energy generation, and is carried out by complexes within the mitochondria. OXPHOS complexes pose a unique challenge for cells because their subunits are encoded on both the nuclear and the mitochondrial genomes. Genomic approaches designed to study nuclear/cytosolic and bacterial gene expression have not been broadly applied to mitochondria, so the co-regulation of OXPHOS genes remains largely unexplored. Here we monitor mitochondrial and nuclear gene expression in Saccharomyces cerevisiae during mitochondrial biogenesis, when OXPHOS complexes are synthesized. We show that nuclear- and mitochondrial-encoded OXPHOS transcript levels do not increase concordantly. Instead, mitochondrial and cytosolic translation are rapidly, dynamically and synchronously regulated. Furthermore, cytosolic translation processes control mitochondrial translation unidirectionally. Thus, the nuclear genome coordinates mitochondrial and cytosolic translation to orchestrate the timely synthesis of OXPHOS complexes, representing an unappreciated regulatory layer shaping the mitochondrial proteome. Our whole-cell genomic profiling approach establishes a foundation for studies of global gene regulation in mitochondria. The genes encoding the subunits of oxidative phosphorylation complexes are split between the nuclear and mitochondrial genomes, but their translation is synchronized by signalling from the cytosol to the mitochondria. Aligning mitochondrial and nuclear expression The OXPHOS (oxidative phosphorylation) complexes within the mitochondrial inner membrane generate the large majority of the cell's energy through the synthesis of ATP from ADP and inorganic phosphate during the oxidation of NADH by molecular oxygen. As the OXPOS complex contains subunits encoded by both the nuclear and the mitochondrial genomes, it has been widely assumed that there must be communication between the two compartments to coordinate gene expression. Stirling Churchman and colleagues have now characterized synthesis of the OXPHOS subunits. They find that nuclear and mitochondrial transcription programs are independently regulated under the direction of the nuclear genome. Regulation occurs not at the level of transcription, but rather in terms of translation, with mitochondrial translation regulated through the cytosolic ribosomes., Author(s): Mary T. Couvillion [sup.1] , Iliana C. Soto [sup.1] , Gergana Shipkovenska [sup.1] , L. Stirling Churchman [sup.1] Author Affiliations: (1) Department of Genetics, Harvard Medical School, Boston, USA [...]

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway. Respiration-dependent cancer stem cells KRAS mutations represent a driver event of pancreatic ductal adenocarcinoma. Targeting this pathway leads to tumour regression, but the frequency of relapse indicates that a fraction of tumour cells survives even in the absence of oncogenic signalling. Using a Kras/p53 mouse model of pancreatic cancer, in which the expression of oncogenic Kras can be switched off, Giulio Draetta and colleagues show that the subpopulation of dormant tumour cells that survives oncogene ablation and is responsible for tumour relapse is dependent on oxidative phosphorylation (OXPHOS) for survival. These cells show high sensitivity to OXPHOS inhibitors, which can inhibit tumour recurrence, suggesting that combined targeting of the KRAS pathway and mitochondrial respiration might be effective in the treatment of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC.sup.1, but targeting mutant KRAS has proved challenging.sup.2. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases.sup.3,4. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling.sup.5,6. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras.sup.1 (Kras.sup.G12D, herein KRas) in a p53.sup.LoxP/WT background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer., Author(s): Andrea Viale [sup.1] [sup.2] , Piergiorgio Pettazzoni [sup.1] [sup.2] , Costas A. Lyssiotis [sup.3] , Haoqiang Ying [sup.1] , Nora Sánchez [sup.1] [sup.2] , Matteo Marchesini [sup.1] [sup.2] , [...]

The 'new' mitochondrial disorders It is now clear that mitochondria serve two fundamental biological roles: the provision of ATP by aerobic respiration, and the mediation of cell death by apoptosis. [...]