Biology subjects

Konishi, A.

Publications and source records attributed to Konishi, A..

4 recordsLinked to original sources

bioRxiv2026

Evaluation of Retinal Safety of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are widely used for the treatment of renal anemia; however, their effects on intraocular vascular endothelial growth factor (VEGF) expression remain unclear. In this study, we examined the effects of all five HIF-PH inhibitors --roxadustat, daprodustat, vadadustat, enarodustat, and molidustat--on Vegfa expression in the retina in mice. C57BL/6J mice were orally administered each inhibitor. Six hours after administration, the kidney, retina, and liver were collected, and transcription levels were quantified by real-time quantitative reverse transcription PCR. Renal Epo transcription was significantly increased by molidustat (P < 0.01), roxadustat (P < 0.01), and enarodustat (P < 0.05). Retinal Vegfa transcription was significantly increased by four inhibitors (P < 0.01), with molidustat showing no significant effect. In the liver, Vegfa transcription was increased by daprodustat (P < 0.05) and vadadustat (P < 0.01). Furthermore, renal Epo and retinal Vegfa transcription levels showed a moderate positive correlation with a marginal trend toward statistical significance (r = 0.37, P = 0.08). These findings indicate that HIF-PH inhibitors differentially regulate hypoxia-responsive genes across tissues and suggest that retinal VEGF upregulation should be considered when evaluating the safety of these agents.

pharmacology and toxicology↗

bioRxiv2025

Loss of STARD7 Impairs Mitochondrial Phospholipid Homeostasis and Contributes to Mitochondrial Myopathy

Mitochondria are composed of phospholipid bilayers rich in phosphatidylcholine (PC). StAR-related lipid transfer domain-containing protein 7 (STARD7) functions as a lipid transfer protein that plays a crucial role in maintaining mitochondrial PC homeostasis. In this study, we investigated the physiological role of STARD7 in skeletal muscle using muscle-specific knockout (mKO) mice. STARD7 expression was markedly higher in the soleus, a mitochondria-dense slow-twitch muscle, compared with fast-twitch fibers. Although muscle fibers from mKO mice exhibited no apparent structural abnormalities, their endurance exercise capacity was markedly reduced. RNA-seq analysis revealed suppressed expression of fast-twitch-related genes accompanied by a reduction in fast-twitch fibers. At the mitochondrial level, respiratory chain complexes remained intact, but oxygen consumption was consistently decreased. Targeted lipidomic analysis showed decreased levels of PC, cardiolipin (CL), and coenzyme Q in mKO mitochondria, particularly in the soleus. Conversely, expression of CL biosynthetic enzymes was unchanged, and an in vitro binding assay indicated that STARD7 preferentially transfers linoleic acid-containing PC required for CL remodeling. Furthermore, electron microscopy revealed disorganized cristae structures, whereas 4-HNE-modified proteins, mtDNA content, and OPA1 processing remained unaffected. Together, these findings demonstrate that STARD7 plays an essential role for maintaining mitochondrial integrity and function in skeletal muscle, and its loss likely contributes to the pathogenesis of mitochondrial myopathy.

biochemistry↗

bioRxiv2024

Branched-chain amino acid metabolism is a crucial modulator of cellular senescence

Cellular senescence is a complex stress response that results in the permanent arrest of cell proliferation. The accumulation of senescent cells occurs during aging in living organisms, and contributes to tissue dysfunction. Although there are growing lines of evidence that various metabolic changes occur in senescent cells, the link between cellular metabolism and senescence is not yet fully understood. In this study, we demonstrate that alterations in the metabolism of branched-chain amino acids (BCAAs) play a crucial role in establishing cellular senescence. Furthermore, we identified mitochondrial BCAA transamination as a crucial step in this process. Our findings show that various types of cellular stress lead to a reduction in the expression of BCAA aminotransferase 2 (BCAT2), one of the BCAA catabolic enzymes, resulting in decreased catabolism of BCAAs and reduced synthesis of glutamate. The reduction of BCAA catabolites, together with the consequent limitation in glutathione production from glutamate, triggers cellular senescence. Furthermore, we demonstrate that a reduction in BCAT2 levels alone is sufficient to induce cellular senescence, both in cultured cells and in mice. Additionally, our results demonstrate that aging alters BCAA metabolism in both mice and humans. Our findings provide new insights into the metabolic mechanisms underlying cellular senescence, with a particular focus on the role of BCAAs.

cell biology↗

bioRxiv2020

Zbtb16 regulates social cognitive behaviors and neocortical development.

Recent genetic studies have underscored the pleiotropic effects of single genes to multiple cognitive disorders. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how the function of ZBTB16 is related to ASD or SCZ remains unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of ZBTB16 in ASD and SCZ.

neuroscience↗