Biology subjects

Kanzaki, M.

Publications and source records attributed to Kanzaki, M..

3 recordsLinked to original sources

bioRxiv2026

Leucine Aminopeptidase 3 Regulates Skeletal Muscle Mitochondrial Homeostasis with Sex-Dependent Metabolic Consequences

Skeletal muscle homeostasis depends on the coordinated regulation of protein turnover and mitochondrial quality control; however, the molecular mechanisms linking these processes remain unclear. In this study, we examined the physiological role of leucine aminopeptidase 3 (LAP3), a post-proteolytic aminopeptidase, using constitutive LAP3-deficient mice. LAP3 deficiency preferentially affected skeletal muscle, causing reduced muscle mass and mitochondrial enlargement in both sexes. Female LAP3-deficient mice also showed reduced myofiber size, impaired endurance capacity, increased energy expenditure, elevated lipid oxidation, and lipid droplet accumulation adjacent to the mitochondria. Proteomic analyses revealed remodeling of pathways related to lipid metabolism and protein homeostasis. Consistent with these findings, LAP3 deficiency increased the expression of Pink1 and Tax1bp1 and promoted the accumulation of ubiquitinated proteins, suggesting alterations in mitochondrial quality control and proteostatic regulation. In cultured myogenic cells, LAP3 localized to mitochondrial fractions, and both LAP3 knockdown and overexpression altered mitochondrial morphology. Taken together, these results identify LAP3 as a regulator of skeletal muscle homeostasis and support a role for LAP3 in linking intracellular peptide turnover to mitochondrial homeostasis, with female skeletal muscle showing greater susceptibility to LAP3 deficiency.

physiology↗

bioRxiv2026

ACE2 associates with insulin-responsive GLUT4 dynamics in adipocytes

Angiotensin-converting enzyme 2 (ACE2) is expressed in adipocytes, yet the mechanisms regulating its intracellular trafficking remain unclear. Here, we investigated whether ACE2 trafficking is coordinated with insulin-responsive vesicle dynamics mediated by the glucose transporter GLUT4 in 3T3L1 adipocytes. Subcellular localization analyses revealed that adipocyte differentiation promotes partial incorporation of ACE2 into insulin-responsive GLUT4-associated vesicular compartments, whereas ACE2 displayed a diffuse distribution in fibroblasts lacking a mature GLUT4 trafficking system. Reconstitution of insulin-responsive GLUT4 vesicle formation through exogenous expression of Sortilin and AS160 in fibroblasts was sufficient to partially recruit ACE2 into perinuclear GLUT4-positive compartments, indicating dependence on canonical GLUT4 vesicle machinery. NanoBiT assays demonstrated a regulated association between ACE2 and GLUT4 that was modestly enhanced by acute insulin stimulation but reduced following prolonged insulin exposure. Insulin stimulation also produced a slight increase in ACE2 surface exposure, while association with GLUT4 was accompanied by reduced ACE2 shedding, suggesting that recruitment into distinct trafficking routes may alter ACE2 accessibility to shedding machinery in adipocytes. Structural modeling further suggested that ACE2 and GLUT4 can form a membrane-compatible complex. Together, these findings indicate that ACE2 trafficking is coordinated with insulin-responsive GLUT4 vesicle dynamics, revealing a previously unrecognized association between metabolic signaling and ACE2 cellular dynamics in adipocytes, with potential implications for metabolic dysfunction and ACE2-associated disease processes.

cell biology↗

bioRxiv2020

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

neuroscience↗