大野 伸彦

Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.

White matter injury is caused by cerebral blood flow disturbances associated with stroke and demyelinating diseases such as multiple sclerosis. Remyelination is induced spontaneously after white matter injury, but progressive multiple sclerosis and white matter stroke are usually characterised by remyelination failure. However, the mechanisms underlying impaired remyelination in lesions caused by demyelination and stroke remain unclear. In the current study, we demonstrated that collagen fibres accumulated in the demyelinated lesions of multiple sclerosis patients (age range 23-80 years) and white matter lesions of stroke patients (age range 80-87 years), suggesting that the accumulation of collagen fibres correlates with remyelination failure in these lesions. To investigate the function of collagen fibres in the white matter lesions, we generated two types of white matter injury in mice. We induced focal demyelination by lysolecithin (LPC) injection and ischemic stroke by endothelin 1 (ET1) injection into the internal capsule. We found that type I collagen fibres were secreted in ET1-induced lesions with impaired white matter regeneration in the chronic phase of disease. We also showed that monocyte-derived macrophages that infiltrated into lesions from the peripheral blood produced type I collagen after white matter injury, and that type I collagen also exacerbated microglial activation, astrogliosis, and axonal injury. Finally, we demonstrated that oligodendrocyte differentiation and remyelination were inhibited in the presence of type I collagen after LPC-induced demyelination. These results suggest that type I collagen secreted by monocyte-derived macrophages inhibited white matter regeneration, and therefore, the modulation of type I collagen metabolism might be a novel therapeutic target for white matter injury.

Neural reflexes to chemicals in the throat protect the airway from aspiration and infection. Mechanistic understanding of these reflexes remains premature, exemplified by chronic cough-a sensitized cough reflex-being a prevalent unmet clinical need. Here, in mice, a whole-body search for channel synapses-featuring CALHM1/3 channel-mediated neurotransmitter release-and single-cell transcriptomics uncovered subclasses of the Pou2f3+ chemosensory cell family in the throat communicating with vagal neurons via this synapse. They express G protein-coupled receptors (GPCRs) for noxious chemicals, T2Rs, which upon stimulation trigger swallow and cough-like expulsive reflexes in the hypopharynx and larynx, respectively. These reflexes were abolished by Calhm3 and Pou2f3 knockout and could be triggered by targeted optogenetic stimulation. Furthermore, aeroallergen exposure augmented CALHM3-dependent expulsive reflex. This study identifies Pou2f3+ epithelial cells with channel synapses as chemosensory end organs of airway protective reflexes and sites of their hyperresponsiveness, advancing mechanistic understanding of airway defense programs with distinct therapeutic potential.

Myelination in the visual pathway is critical for transmitting visual information from retina to the brain. Reducing visual experience shortens myelin sheath length and slows the conduction velocity of the optic nerve. However, the mechanism underlying such experience-dependent myelination is unclear. Here, we found that closing both eyes, binocular deprivation (BD), during the juvenile period less affects the optic nerve myelination than monocular deprivation (MD) via GABA signaling. RNA-seq analysis of optic nerves from MD and BD mice revealed that GABAergic signaling is downregulated on the deprived side of MD compared to the intact side and BD. Inhibition of GABAergic signaling during the juvenile period resulted in myelin sheath shortening and excessive oligodendrocyte generation in normal mice, similar to the changes observed in MD mice. Enhancing GABAergic signaling rescued the myelin sheath shortening and excessive oligodendrocyte generation in the optic nerve of MD mice. Furthermore, we identified novel GABAergic neurons located within the optic nerve, whose neurites form belt-like presynaptic structures with the oligodendrocyte lineage cells, suggesting a potential source of the GABAergic inputs into oligodendrocytes. Our results indicate that the myelination of visual pathway is maintained by binocular visual inputs via intra-nerve GABA signaling.

This study developed a three-dimensional ultrastructural analysis application using serial block-face scanning electron microscopy (SBF-SEM) to investigate surgically acquired human skin tissues containing the arrector pili muscle. We utilized the en bloc staining, including reduced osmium, thiocarbohydrazide, and lead aspartate, as well as the embedding using a carbon-based conductive resin. Next, we obtained serial images with SBF-SEM. The results revealed dense nerve fiber networks branching from nearby nerve fiber bundles outside the muscle and running among muscle fibers. Additionally, the dense nerve network running through and along arrector pili muscle fibers rarely penetrates the connective tissues between smooth muscle fibers and epithelial cells. Furthermore, in the observation area, no individual smooth muscle fibers formed adhesion structures with the epithelial cells of the hair follicle, ending in the dermal extracellular matrix near the epithelial cells. These results indicate the usefulness of this approach for three-dimensional ultrastructural analyses of human skin tissues comprising follicular units and revealing structural changes in skin tissues, especially the arrector pili muscle and nerve fibers with hair follicular epithelium, in aging and diseased conditions.