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Local metabolic demand within cells varies widely and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of MICOS, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery that we term "METEORs". METEORs have a unique composition; MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.
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PPTC7 is a mitochondrial-localized phosphatase that suppresses BNIP3- and NIX-mediated mitophagy, but the mechanisms underlying this regulation remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. Loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels, which requires an intact catalytic motif but is surprisingly independent of its targeting to mitochondria. Consistently, we find that PPTC7 is dual-localized to the outer mitochondrial membrane and the matrix. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments demonstrate that PPTC7 dynamically associates with BNIP3 and NIX within the native cellular environment. Collectively, these data reveal that a fraction of PPTC7 localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX, limiting basal mitophagy.
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Proteínas de Membrana , Mitocôndrias , Membranas Mitocondriais , Proteínas Mitocondriais , Mitofagia , Proteínas Proto-Oncogênicas , Mitofagia/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Humanos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Células HeLa , AnimaisRESUMO
With breast cancer being one of the most widespread causes of death for women, there is an unmet need for its early detection. For this purpose, we propose a non-invasive approach based on X-ray scattering. We measured samples from 107 unique patients provided by the Breast Cancer Now Tissue Biobank, with the total dataset containing 2958 entries. Two different sample-to-detector distances, 2 and 16 cm, were used to access various structural biomarkers at distinct ranges of momentum transfer values. The biomarkers related to lipid metabolism are consistent with those of previous studies. Machine learning analysis based on the Random Forest Classifier demonstrates excellent performance metrics for cancer/non-cancer binary decisions. The best sensitivity and specificity values are 80% and 92%, respectively, for the sample-to-detector distance of 2 cm and 86% and 83% for the sample-to-detector distance of 16 cm.
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Bacillus subtilis is a beneficial bacterium that supports plant growth and protects plants from bacterial, fungal, and viral infections. Using a simplified system of B. subtilis and Arabidopsis thaliana interactions, we studied the fitness and transcriptome of bacteria detached from the root over generations of growth in LB medium. We found that bacteria previously associated with the root or exposed to its secretions had greater stress tolerance and were more competitive in root colonization than bacteria not previously exposed to the root. Furthermore, our transcriptome results provide evidence that plant secretions induce a microbial stress response and fundamentally alter signaling by the cyclic nucleotide c-di-AMP, a signature maintained by their descendants. The changes in cellular physiology due to exposure to plant exudates were multigenerational, as they allowed not only the bacterial cells that colonized a new plant but also their descendants to have an advance over naive competitors of the same species, while the overall plasticity of gene expression and rapid adaptation were maintained. These changes were hereditary but not permanent. Our work demonstrates a bacterial memory manifested by multigenerational reversible adaptation to plant hosts in the form of activation of the stressosome, which confers an advantage to symbiotic bacteria during competition.
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Arabidopsis , Bacillus subtilis , Raízes de Plantas , Simbiose , Bacillus subtilis/genética , Bacillus subtilis/fisiologia , Arabidopsis/microbiologia , Arabidopsis/genética , Raízes de Plantas/microbiologia , Transcriptoma , Estresse Fisiológico , Regulação Bacteriana da Expressão Gênica , Adaptação Fisiológica/genéticaRESUMO
INTRODUCTION: Genitourinary (GU) trauma resulting from combat and the treatment of these injuries is an inadequately explored subject. While historically accounting for 2 to 5% of combat-related injuries, GU-related injuries escalated considerably during U.S. involvements in Iraq and Afghanistan due to improvised explosive devices (IEDs). Advanced body armor increased survivability while altering injury patterns, with a shift toward bladder and external genitalia injuries. Forward-deployed surgeons and military medics manage treatment, with Role 2 facilities addressing damage control resuscitation and surgery, including GU-specific procedures. The review aims to provide an overview of GU trauma and enhance medical readiness for battlefield scenarios. MATERIALS AND METHODS: This review examined urologic trauma management in combat, searching PubMed, Cochrane Central, Scopus, and Web of Science databases with search terms "wounds" OR "injuries" OR "hemorrhage" AND "trauma" AND "penile" OR "genital" AND "combat." Records were then screened for inclusion of combat-related urologic trauma in conflicts after 2001 and which were English-based publications. No limits based on year of publication, study design, or additional patient-specific demographics were implemented in this review. RESULTS: Ultimately, 33 articles that met the inclusion criteria were included. Included texts were narrowed to focus on the management of renal injuries, ureteral trauma, bladder injuries, penile amputations, urethral injuries, testicular trauma, Central nervous system (CNS) injuries, and female GU injuries. CONCLUSIONS: In modern conflicts, treatment of GU trauma at the point of injury should be secondary to Advanced Trauma Life Support (ATLS) care in addition to competing non-medical priorities. This review highlights the increasing severity of GU trauma due to explosive use, especially dismounted IEDs. Concealed morbidity and fertility issues underscore the importance of protection measures. Military medics play a crucial role in evaluating and managing GU injuries. Adherence to tactical guidelines and trained personnel is vital for effective management, and GU trauma's integration into broader polytrauma care is essential. Adequate preparation should address challenges for deploying health care providers, prioritizing lifesaving and quality-of-life care for casualties affected by GU injuries.
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Microbial communities are fundamental to every ecosystem on Earth and hold great potential for biotechnological applications. However, their complex nature hampers our ability to study and understand them. A common strategy to tackle this complexity is to abstract the community into a network of interactions between its members - a phenomenological description that captures the overall effects of various chemical and physical mechanisms that underpin these relationships. This approach has proven useful for numerous applications in microbial ecology, including predicting community dynamics and stability and understanding community assembly and evolution. However, care is required in quantifying and interpreting interactions. Here, we clarify the concept of an interaction and discuss when interaction measurements are useful despite their context-dependent nature. Furthermore, we categorize different approaches for quantifying interactions, highlighting the research objectives each approach is best suited for.
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Interações Microbianas , Ecossistema , Microbiota , Bactérias/metabolismo , Bactérias/genéticaRESUMO
Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial contact site and cristae organizing system (MICOS) complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae-shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe, a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS to promote normal mitochondrial morphology and respiratory function. Mmc1 is a distant relative of the dynamin superfamily of proteins (DSPs), GTPases, which are well established to shape and remodel membranes. Similar to DSPs, Mmc1 self-associates and forms high-molecular-weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting that it does not dynamically remodel membranes. These data are consistent with the model that Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.
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Membranas Mitocondriais , Proteínas Mitocondriais , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Dinaminas/metabolismo , Dinaminas/genética , Mitocôndrias/metabolismo , Membranas Associadas à MitocôndriaRESUMO
Fungal phytopathogens cause significant reductions in agricultural yields annually, and overusing chemical fungicides for their control leads to environmental pollution and the emergence of resistant pathogens. Exploring natural isolates with strong antagonistic effects against pathogens can improve our understanding of their ecology and develop new treatments for the future. We isolated and characterized a novel bacterial strain associated with the species Burkholderia cenocepacia, termed APO9, which strongly inhibits Zymoseptoria tritici, a commercially important pathogenic fungus causing Septoria tritici blotch in wheat. Additionally, this strain exhibits inhibitory activity against four other phytopathogens. We found that physical contact plays a crucial role for APO9's antagonistic capacity. Genome sequencing of APO9 and biosynthetic gene cluster (BGC) analysis identified nine classes of BGCs and three types of secretion systems (types II, III, and IV), which may be involved in the inhibition of Z. tritici and other pathogens. To identify genes driving APO9's inhibitory activity, we screened a library containing 1,602 transposon mutants and identified five genes whose inactivation reduced inhibition efficiency. One such gene encodes for a diaminopimelate decarboxylase located in a terpenoid biosynthesis gene cluster. Phylogenetic analysis revealed that while some of these genes are also found across the Burkholderia genus, as well as in other Betaproteobacteria, the combination of these genes is unique to the Burkholderia cepacia complex. These findings suggest that the inhibitory capacity of APO9 is complex and not limited to a single mechanism, and may play a role in the interaction between various Burkholderia species and various phytopathogens within diverse plant ecosystems. IMPORTANCE: The detrimental effects of fungal pathogens on crop yields are substantial. The overuse of chemical fungicides contributes not only to environmental pollution but also to the emergence of resistant pathogens. Investigating natural isolates with strong antagonistic effects against pathogens can improve our understanding of their ecology and develop new treatments for the future. We discovered and examined a unique bacterial strain that demonstrates significant inhibitory activity against several phytopathogens. Our research demonstrates that this strain has a wide spectrum of inhibitory actions against plant pathogens, functioning through a complex mechanism. This plays a vital role in the interactions between plant microbiota and phytopathogens.
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Ascomicetos , Burkholderia cenocepacia , Doenças das Plantas , Ascomicetos/genética , Burkholderia cenocepacia/genética , Burkholderia cenocepacia/efeitos dos fármacos , Doenças das Plantas/microbiologia , Triticum/microbiologia , Antibiose , Família MultigênicaRESUMO
Mitochondria are highly dynamic double membrane-bound organelles that exist in a semi-continuous network. Mitochondrial morphology arises from the complex interplay of numerous processes, including opposing fission and fusion dynamics and the formation of highly organized cristae invaginations of the inner membrane. While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear how fission is coordinated across two membrane bilayers and how mitochondrial inner membrane organization is coupled with mitochondrial fission dynamics. Previously, the yeast protein Mdm33 was implicated in facilitating fission by coordinating with inner membrane homeostasis pathways. However, Mdm33 is not conserved outside fungal species and its precise mechanistic role remains unclear. Here, we use a bioinformatic approach to identify a putative structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK). We find that the mitochondrial phenotypes associated with altered CCDC51 levels implicate the protein in mitochondrial fission dynamics. Further, using timelapse microscopy, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 can partially rescue yeast Δmdm33 cells, indicating the proteins are functionally analogous. Our data reveal that Mdm33/CCDC51 are conserved mediators of mitochondrial morphology and suggest the proteins play a crucial role in maintaining normal mitochondrial dynamics and organelle homeostasis.
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Plasmids are pivotal in driving bacterial evolution through horizontal gene transfer. Here, we investigated 3467 human gut microbiome samples across continents and disease states, analyzing 11,086 plasmids. Our analyses reveal that plasmid dispersal is predominantly stochastic, indicating neutral processes as the primary driver of their wide distribution. We find that only 20-25% of plasmid DNA is being selected in various disease states, constraining its distribution across hosts. Selective pressures shape specific plasmid segments with distinct ecological functions, influenced by plasmid mobilization lifestyle, antibiotic usage, and inflammatory gut diseases. Notably, these elements are more commonly shared within groups of individuals with similar health conditions, such as Inflammatory Bowel Disease (IBD), regardless of geographic location across continents. These segments contain essential genes such as iron transport mechanisms- a distinctive gut signature of IBD that impacts the severity of inflammation. Our findings shed light on mechanisms driving plasmid dispersal and selection in the human gut, highlighting their role as carriers of vital gene pools impacting bacterial hosts and ecosystem dynamics.
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Ecossistema , Doenças Inflamatórias Intestinais , Humanos , Plasmídeos/genética , Bactérias/genética , Antibacterianos , Transferência Genética Horizontal , Doenças Inflamatórias Intestinais/genéticaRESUMO
Current first-line therapies for seizure management recommend benzodiazepines, which target gamma-aminobutyric acid type A channels to stop the seizure activity. However, seizures may be refractory to traditional first-line therapies, transitioning into status epilepticus and becoming resistant to gamma-aminobutyric acid type A augmenting drugs. Although there are other antiseizure medications available for clinicians to use in the intensive care unit, these options can be less readily available outside of the intensive care unit and entirely absent in the prehospital setting. Instead, patients frequently receive multiple doses of first-line agents with increased risk of hemodynamic or airway collapse. Ketamine is readily available in the prehospital setting and emergency department, has well-established antiseizure effects with a favorable safety profile, and is a drug often used for several other indications. This article aimed to explore the utilization of ketamine for seizure management in the prehospital setting, reviewing seizure pathophysiology, established treatment mechanisms of action and pharmacokinetics, and potential benefits of early ketamine use in status epilepticus.
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Ketamina , Estado Epiléptico , Humanos , Ketamina/uso terapêutico , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Convulsões/tratamento farmacológico , Serviço Hospitalar de Emergência , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Mitochondria are commonly perceived as "cellular power plants". Intriguingly, power conversion is not their only function. In the first part of this paper, we review the role of mitochondria in the evolution of eukaryotic organisms and in the regulation of the human body, specifically focusing on cancer and autism in relation to mitochondrial dysfunction. In the second part, we overview our previous works, revealing the physical principles of operation for proton-pumping complexes in the inner mitochondrial membrane. Our proposed simple models reveal the physical mechanisms of energy exchange. They can be further expanded to answer open questions about mitochondrial functions and the medical treatment of diseases associated with mitochondrial disorders.
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Mitocôndrias , Membranas Mitocondriais , Humanos , Mitocôndrias/fisiologia , Membranas Mitocondriais/metabolismo , Bombas de Próton/metabolismo , Física , BiologiaRESUMO
PPTC7 is a mitochondrial-localized PP2C phosphatase that maintains mitochondrial protein content and metabolic homeostasis. We previously demonstrated that knockout of Pptc7 elevates mitophagy in a BNIP3- and NIX-dependent manner, but the mechanisms by which PPTC7 influences receptor-mediated mitophagy remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. On a molecular level, loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels in response to pseudohypoxia, a well-known inducer of mitophagy. This PPTC7-mediated suppression of BNIP3 and NIX protein expression requires an intact PP2C catalytic motif but is surprisingly independent of its mitochondrial targeting, indicating that PPTC7 influences mitophagy outside of the mitochondrial matrix. We find that PPTC7 exists in at least two distinct states in cells: a longer isoform, which likely represents full length protein, and a shorter isoform, which likely represents an imported, matrix-localized phosphatase pool. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments suggest that PPTC7 associates with BNIP3 and NIX within the native cellular environment. Importantly, these associations are enhanced in cellular conditions that promote BNIP3 and NIX turnover, demonstrating that PPTC7 is dynamically recruited to BNIP3 and NIX to facilitate their degradation. Collectively, these data reveal that a fraction of PPTC7 dynamically localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX.
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Microbial communities drive global biogeochemical cycles and shape the health of plants and animals-including humans. Their structure and function are determined by ecological and environmental interactions that govern the assembly, stability and evolution of microbial communities. A widely held view is that antagonistic interactions such as competition predominate in microbial communities and are ecologically more important than synergistic interactions-for example, mutualism or commensalism. Over the past decade, however, a more nuanced picture has emerged, wherein bacteria, archaea and fungi exist within interactive networks in which they exchange essential and non-essential metabolites. These metabolic interactions profoundly impact not only the physiology, ecology and evolution of the strains involved, but are also central to the functioning of many, if not all, microbiomes. Therefore, we advocate for a balanced view of microbiome ecology that encompasses both synergistic and antagonistic interactions as key forces driving the structure and dynamics within microbial communities.
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Microbiota , Animais , Humanos , Simbiose , Bactérias/genética , Bactérias/metabolismo , ArchaeaRESUMO
Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial inner membrane-localized MICOS complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe, a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS complexes to promote normal mitochondrial morphology and respiratory function. Bioinformatic analyses reveal that Mmc1 is a distant relative of the Dynamin-Related Protein (DRP) family of GTPases, which are well established to shape and remodel membranes. We find that, like DRPs, Mmc1 self-associates and forms high molecular weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting it does not dynamically remodel membranes. These data are consistent with a model in which Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.
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PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
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Proteínas Mitocondriais , Mitofagia , Animais , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mitofagia/genética , Fibroblastos/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Monoéster Fosfórico Hidrolases/metabolismoRESUMO
Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
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Dinâmica Mitocondrial , Proteínas Mitocondriais , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Dinaminas/genética , Dinaminas/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismoRESUMO
Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by the dynamin-related protein Dnm1 (Drp1 in humans), a large GTPase that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity alone is sufficient to complete fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1. Loss of Mdi1 leads to hyper-fused mitochondria networks due to defects in mitochondrial fission, but not lack of Dnm1 recruitment to mitochondria. Mdi1 plays a conserved role in fungal species and its homologs contain a putative amphipathic α-helix, mutations in which disrupt mitochondrial morphology. One model to explain these findings is that Mdi1 associates with and distorts the mitochondrial inner membrane to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of a protein that resides inside mitochondria.
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Predicting interspecies interactions is a key challenge in microbial ecology given that interactions shape the composition and functioning of microbial communities. However, predicting microbial interactions is challenging because they can vary considerably depending on species' metabolic capabilities and environmental conditions. Here, we employ machine learning models to predict pairwise interactions between culturable bacteria based on their phylogeny, monoculture growth capabilities, and interactions with other species. We trained our models on one of the largest available pairwise interactions data set containing over 7,500 interactions between 20 species from two taxonomic groups that were cocultured in 40 different carbon environments. Our models accurately predicted both the sign (accuracy of 88%) and the strength of effects (R2 of 0.87) species had on each other's growth. Encouragingly, predictions with comparable accuracy could be made even when not relying on information about interactions with other species, which are often hard to measure. However, species' monoculture growth was essential to the model, as predictions based solely on species' phylogeny and inferred metabolic capabilities were significantly less accurate. These results bring us one step closer to a predictive understanding of microbial communities, which is essential for engineering beneficial microbial consortia. IMPORTANCE In order to understand the function and structure of microbial communities, one must know all pairwise interactions that occur between the different species within the community, as these interactions shape the community's structure and functioning. However, measuring all pairwise interactions can be an extremely difficult task especially when dealing with big complex communities. Because of that, predicting interspecies interactions is a key challenge in microbial ecology. Here, we use machine learning models in order to accurately predict the type and strength of interactions. We trained our models on one of the largest available pairwise interactions data set, containing over 7,500 interactions between 20 different species that were cocultured in 40 different environments. Our results show that, in general, accurate predictions can be made, and that the ability of each species to grow on its own in the given environment contributes the most to predictions. Being able to predict microbial interactions would put us one step closer to predicting the functionality of microbial communities and to rationally microbiome engineering.
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Bactérias , Microbiota , Bactérias/genética , Consórcios Microbianos , Interações Microbianas , Microbiota/genéticaRESUMO
Mitochondria play critical roles in cellular metabolism and to maintain their integrity, they are regulated by several quality control pathways, including mitophagy. During BNIP3/BNIP3L-dependent receptor-mediated mitophagy, mitochondria are selectively targeted for degradation by the direct recruitment of the autophagy protein LC3. BNIP3 and/or BNIP3L are upregulated situationally, for example during hypoxia and developmentally during erythrocyte maturation. However, it is not well understood how they are spatially regulated within the mitochondrial network to locally trigger mitophagy. Here, we find that the poorly characterized mitochondrial protein TMEM11 forms a complex with BNIP3 and BNIP3L and co-enriches at sites of mitophagosome formation. We find that mitophagy is hyper-active in the absence of TMEM11 during both normoxia and hypoxia-mimetic conditions due to an increase in BNIP3/BNIP3L mitophagy sites, supporting a model that TMEM11 spatially restricts mitophagosome formation.