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1.
Commun Biol ; 5(1): 418, 2022 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-35513471

RESUMEN

Biologically realistic computer simulations of neuronal circuits require systematic data-driven modeling of neuron type-specific synaptic activity. However, limited experimental yield, heterogeneous recordings conditions, and ambiguous neuronal identification have so far prevented the consistent characterization of synaptic signals for all connections of any neural system. We introduce a strategy to overcome these challenges and report a comprehensive synaptic quantification among all known neuron types of the hippocampal-entorhinal network. First, we reconstructed >2600 synaptic traces from ∼1200 publications into a unified computational representation of synaptic dynamics. We then trained a deep learning architecture with the resulting parameters, each annotated with detailed metadata such as recording method, solutions, and temperature. The model learned to predict the synaptic properties of all 3,120 circuit connections in arbitrary conditions with accuracy approaching the intrinsic experimental variability. Analysis of data normalized and completed with the deep learning model revealed that synaptic signals are controlled by few latent variables associated with specific molecular markers and interrelating conductance, decay time constant, and short-term plasticity. We freely release the tools and full dataset of unitary synaptic values in 32 covariate settings. Normalized synaptic data can be used in brain simulations, and to predict and test experimental hypothesis.


Asunto(s)
Aprendizaje Profundo , Corteza Entorrinal , Hipocampo/fisiología , Neuronas/fisiología , Sinapsis/fisiología
2.
J Physiol ; 600(3): 547-567, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34837710

RESUMEN

Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the least shrew (Cryptotis parva). This was achieved through a combination of high-resolution 3D focused ion beam electron microscopy imaging and tandem mass tag mass spectrometry proteomics. We demonstrate that liver and kidney mitochondrial content are equivalent to the heart, permitting assessment of mitochondrial adaptations in different organs with similar metabolic demand. Muscle mitochondrial networks (cardiac and skeletal) are extensive, with a high incidence of nanotunnels - which collectively support the metabolism of large muscle cells. Mitochondrial networks were not detected in the liver and kidney as individual mitochondria are localized with sites of ATP consumption. This configuration is not observed in striated muscle, likely due to a homogeneous ATPase distribution and the structural requirements of contraction. These results demonstrate distinct, fundamental mitochondrial structural adaptations for similar metabolic demand that are dependent on the topology of energy utilization process in a mammalian model of extreme metabolism. KEY POINTS: Least shrews were studied to explore the relationship between metabolic function, mitochondrial morphology and protein content in different tissues. Liver and kidney mitochondrial content and enzymatic activity approaches that of the heart, indicating similar metabolic demand among tissues that contribute to basal and maximum metabolism. This allows an examination of mitochondrial structure and composition in tissues with similar maximum metabolic demands. Mitochondrial networks only occur in striated muscle. In contrast, the liver and kidney maintain individual mitochondria with limited reticulation. Muscle mitochondrial reticulation is the result of dense ATPase activity and cell-spanning myofibrils which require networking for adequate metabolic support. In contrast, liver and kidney ATPase activity is localized to the endoplasmic reticulum and basolateral membrane, respectively, generating a locally balanced energy conversion and utilization. Mitochondrial morphology is not driven by maximum metabolic demand, but by the cytosolic distribution of energy-utilizing systems set by the functions of the tissue.


Asunto(s)
Músculo Estriado , Musarañas , Animales , Metabolismo Energético/fisiología , Mitocondrias/metabolismo , Músculo Esquelético/fisiología , América del Norte , Musarañas/anatomía & histología
3.
J Cell Biol ; 219(7)2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32375181

RESUMEN

Although mitochondrial DNA (mtDNA) is prone to accumulate mutations and lacks conventional DNA repair mechanisms, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations is restricted through the maternal lineage is debated. Here, we demonstrate that mitochondrial fission, together with the lack of mtDNA replication, segregate mtDNA into individual organelles in the Drosophila early germarium. After mtDNA segregation, mtDNA transcription begins, which activates respiration. Mitochondria harboring wild-type genomes have functional electron transport chains and propagate more vigorously than mitochondria containing deleterious mutations in hetreoplasmic cells. Therefore, mtDNA expression acts as a stress test for the integrity of mitochondrial genomes and sets the stage for replication competition. Our observations support selective inheritance at the organelle level through a series of developmentally orchestrated mitochondrial processes. We also show that the Balbiani body has a minor role in mtDNA selective inheritance by supplying healthy mitochondria to the pole plasm. These two mechanisms may act synergistically to secure the transmission of functional mtDNA through Drosophila oogenesis.


Asunto(s)
ADN Mitocondrial/genética , Drosophila melanogaster/genética , Genes Mitocondriales , Genoma Mitocondrial , Oocitos/metabolismo , Oogénesis/genética , Animales , Respiración de la Célula/genética , Replicación del ADN , ADN Mitocondrial/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Transporte de Electrón , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Mitocondrias , Dinámicas Mitocondriales , Mutación , Oocitos/citología , Oocitos/crecimiento & desarrollo
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