Spatial and morphological organization of mitochondria in neurons across a connectome

Mitochondria are essential for neuronal function, yet how they are spatially and structurally organized across different neuron types has remained unclear. Researchers analyzed electron microscopy connectome data from Drosophila to map hundreds of thousands of mitochondria across thousands of neurons, then validated key findings using a mouse visual cortex connectome. They found that mitochondrial size and shape vary systematically with cell type and neurotransmitter identity, offering a potential marker for classifying neurons. Mitochondria are positioned within 2–3 micrometers of synapses and other structural landmarks, with consistent placement patterns that differ across neuron types and cellular compartments. Their distribution also correlates with local neural activity levels and the identity of postsynaptic partners. The mouse data confirmed cell type–specific morphology but revealed partly different positioning rules, suggesting both conserved and species-specific organizational logic. Overall, the work reframes mitochondria as organelles whose arrangement is tightly integrated with circuit-level brain architecture.

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From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus

Chronic pain frequently co-occurs with depression and anxiety, but the brain mechanisms connecting persistent sensory disturbance to emotional dysregulation are poorly understood. Combining human neuroimaging data from the UK Biobank with rodent experiments, researchers identified a two-phase pattern of hippocampal change. Early in the pain course, hippocampal volume actually grew and cognition temporarily improved; with the onset of depression, volume subsequently fell. In rodents, the dentate gyrus emerged as a critical transition point — lesioning it prevented affective symptoms from developing. Overactive newborn neurons in this region recruited and reshaped microglia, disrupting local circuit balance. Silencing the newborn neurons relieved emotional symptoms but harmed cognition, whereas targeting microglia specifically restored mood-related behavior without that cognitive trade-off. The work identifies microglial remodeling in the hippocampal dentate gyrus as a pivotal mechanism through which chronic pain tips into mood disorders, and points to microglia as a therapeutically promising target.

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Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering

Tumor cells often evade immune attack because T cells that recognize cancer-related self-proteins have been weakened by central tolerance mechanisms during development. Researchers targeted this problem by engineering a T cell receptor (TCR) specific for prostatic acid phosphatase, a nonmutated prostate tumor antigen, using mechanical force biology as their guide. They pinpointed a "catch-bond hotspot" — a position where a single amino acid substitution extended how long the TCR stays bound to its peptide-MHC target under mechanical load, without altering overall binding affinity or antigen selectivity. T cells carrying these modified receptors expanded more robustly in tumors, adopted stronger effector profiles, and cleared tumors more effectively. Structural studies and molecular dynamics simulations showed the mutation works by reorganizing water molecules at the binding interface, better priming the TCR for peptide engagement. The findings establish catch-bond engineering as a practical strategy for converting tolerance-dampened T cells into potent cancer cell killers for TCR-based therapies.

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