Masafumi Noguchi

Wakayama Medical University

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Luca Scorrano

Veneto Institute of Molecular Medicine

Atsuko Kasahara

Kanazawa University

Norihito Shintani

Wakayama Medical University

Keitaro Shibata

Tokushima University

Takashi Kohno

National Cancer Centre Japan

Chiaki Takahashi

Kyushu University

Susumu Kohno

Kanazawa University

Noriko Gotoh

Kanazawa University

Yukino Machida

Nippon Veterinary and Life Science University

Atsushi Hirao

Jichi Medical University

Cooperative Institutions

University of Padua

Osaka University

Kanazawa University

Veneto Institute of Molecular Medicine

Tohoku University

The University of Tokyo

Wakayama Medical University

Dulbecco Telethon Institute

Spanish National Centre for Cardiovascular Research

Tokushima University

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Mitochondrial Transplantation in Animal Models of Psychiatric Disorders: A Novel Approach to Psychiatric Treatment

Biomolecules (2025)

Keiko Iwata Masafumi Noguchi Norihito Shintani

Mitochondria are essential for brain function, and accumulating evidence from postmortem brain studies, neuroimaging, and basic research indicates mitochondrial impairments in patients with psychiatric disorders. Restoring mitochondrial function therefore represents a promising therapeutic strategy for these conditions. Mitochondrial transplantation, an innovative approach that uses functional mitochondria to repair damaged cells, has demonstrated efficacy through various delivery methods in cell, animal, and animal disease models. This review explores the critical link between mitochondria and psychiatric disorders and provides an overview of mitochondrial transplantation as a therapeutic intervention. It highlights recent advances in mitochondrial transplantation in animal models of psychiatric disorders, focusing on delivery methods, the timing of administration, and the integration of exogenous mitochondria into brain cells. The potential therapeutic effects and the mechanisms that underlie these effects are discussed. Additionally, this review evaluates the clinical relevance, challenges, and future strategies for the application of mitochondrial transplantation in the treatment of psychiatric disorders.

Therapeutic approach

10.3390/biom15020184

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Mitochondrial fusion factor OPA1 sustains gefitinib-resistance in lung adenocarcinoma cells

Proceedings for Annual Meeting of The Japanese Pharmacological Society (2021)

Masafumi Noguchi Susumu Kohno Keitaro Shibata Takashi Kohno Noriko Gotoh

Mitochondria are the organelle responsible for energy production even in cancer cells; however, their roles in chemoresistance remain unclear. Here we show that mitochondrial fusion factor OPA1 is required to maintain the resistance against gefitinib, an EGFR tyrosine kinase inhibitor, in lung adenocarcinoma cells (LUADs). The gefitinib-resistant LUADs highly expressed OPA1, resulting in the elongation of mitochondria with abnormal cristae structure. The overexpressed OPA1 conferred enhanced mitochondrial respiration and anti-apoptotic activity to gefitinib-resistant LUADs. Genetic knockdown or pharmacological inhibition of OPA1 restored the gefitinib sensitivity and induced apoptosis in the resistant LUADs. Furthermore, inhibition of mitochondrial respiration efficiently restored their gefitinib-sensitivity. Thus, inner mitochondrial protein OPA1 and mitochondrial respiration are the downstream factors to sustain the gefitinib resistance. Our results suggest that OPA1 may serve as a novel therapeutic target to overcome chemoresistance in LUADs.

10.1254/jpssuppl.94.0_2-p2-lb50

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Exploring the role of mitochondrial dynamics in tracheal stem cell

The Molecular Biology Society of Japan (2019)

Masafumi Noguchi Atsuko Kasahara Luca Scorrano

Dynamics

Source

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Mitochondrial cristae: lung cancer metabolism architects

Life Metabolism (2023)

Masafumi Noguchi Luca Scorrano

In a recent study published in Nature, Shackelford and colleagues use an innovative in vivo mitochondrial morphology and bioenergetics analysis pipeline to correlate the metabolic signature of non-small cell lung cancer subtypes to the ultrastructure of mitochondria and their contact sites with lipid droplets. This study paves the way for diagnostic and therapeutic protocols for lung cancer based on the rationale assessment and modulation of mitochondrial topology and ultrastructure.

Bioenergetics

10.1093/lifemeta/load015

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Possible roles of mitochondrial protein p13 in the control of white adipose tissue amount

Proceedings for Annual Meeting of The Japanese Pharmacological Society (2023)

Masafumi Noguchi Satomi Hara Keiko Iwata Hitoshi Hashimoto Norihito Shintani

Mitochondria are involved in various cellular functions such as energy production and apoptosis, and their dysfunction has been regarded as one of the causes of metabolic disorders such as diabetes. We recently identified the mitochondrial protein p13 with a molecular weight of 13 kDa based on the decreased expression in pancreatic islets of Langerhans in type II diabetic mice, and have been conducting research using systemically deficient mice (p13-/- mice). Here, we investigated the role of p13 in white adipose tissue (WAT) pathophysiology via multiscale omics analyses in vivo and in vitro. First, we measured the weight of various tissues in the whole body and found that the weight of white adipose tissue was markedly decreased in p13-/- mice. Moreover, as a result of comprehensive histochemical analysis, selective and marked abnormalities were observed in p13-/- WAT compared to the other tissues, and especially, a marked reduction in the size of adipocytes and lipid droplets were observed. Besides, RNA-seq and qRT-PCR analyses revealed decreases in lipid synthesis genes and increases in lipid degradation genes in p13-/- WAT, suggesting the role of p13 in lipid metabolism. In contrast, there was no significant difference in adipose differentiation marker genes, and we also confirmed that p13 deficiency did not affect adipose differentiation in an adipocyte differentiation model using mouse embryonic fibroblasts (MEFs). Serum parameter analysis revealed high levels of total ketone bodies and low levels of blood glucose, lipase, triglycerides, and HDL-C. Besides, p13-/- mice had lower steady-state insulin levels and lower levels of insulin-antagonizing corticosterone. Taken together, the present results suggest that WAT is markedly decreased in p13-/- mice due to abnormal hormone homeostasis, and that endogenous p13 may play an important role in regulating hormon release and lipid metabolism.

Lipid droplet

FGF21

Thermogenin

10.1254/jpssuppl.97.0_3-b-o13-4

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Region-specific regulation of cell proliferation by FGF receptor signaling during the Wolffian duct development

Developmental Biology (2015)

Mika Okazawa Aki Murashima Masayo Harada Naomi Nakagata Masafumi Noguchi

The Wolffian duct (WD) is a primordium of the male reproductive tract and kidney collecting duct system. Fibroblast growth factor receptors (FGFRs), members of the receptor tyrosine kinase (RTK) family, are essential for kidney development. Although the functions of FGFR signaling in kidney morphogenesis have been analyzed, their function in WD development has not been comprehensively investigated. Here, we demonstrate that Fgfr2 is the major Fgfr gene expressed throughout the WD epithelia and that it is essential for the maintenance of the WD, specifically in the caudal part of the WD. Hoxb7-Cre mediated inactivation of Fgfr2 in the mouse WD epithelia resulted in the regression of the caudal part of the WD and abnormal male reproductive tract development. Cell proliferation and expression of the downstream target genes of RTK signaling (Etv4 and Etv5) were decreased in the caudal part of the WD epithelia in the mutant embryos. Cranial (rostral) WD formation and ureteric budding were not affected. Ret, Etv4, and Etv5 expression were sustained in the ureteric bud of the mutant embryos. Taken together, these data suggest region-specific requirements for FGFR2 signaling in the developing caudal WD epithelia.

Mesonephric duct

Ureteric bud

Primordium

10.1016/j.ydbio.2015.01.023

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Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies

Cell Reports (2015)

Masafumi Noguchi Kenta Sumiyama Mitsuru Morimoto

The airway epithelium consists of diverse cell types, including neuroendocrine (NE) cells. These cells are thought to function as chemoreceptors and as a component of the stem cell niche as well as the cells of origin in small-cell lung cancer. NE cells often localize at bifurcation points of airway tubes, forming small clusters called neuroepithelial bodies (NEBs). To investigate NEB development, we established methods for 3D mapping and ex vivo 4D imaging of developing lungs. We found that NEBs localize at stereotypic positions in the bifurcation area irrespective of variations in size. Notch-Hes1 signaling contributes to the differentiation of solitary NE cells, regulating their number but not localization. Live imaging revealed that individual NE cells migrate distally to and cluster at bifurcation points, driving NEB formation. We propose that NEB development is a multistep process involving differentiation of individual NE cells and their directional migration to organize NEBs.

Neuroepithelial cell

10.1016/j.celrep.2015.11.058

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Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line

Cell Death and Disease (2023)

Masafumi Noguchi Susumu Kohno Anna Pellattiero Yukino Machida Keitaro Shibata

Drug resistance limits the efficacy of chemotherapy and targeted cancer treatments, calling for the identification of druggable targets to overcome it. Here we show that the mitochondria-shaping protein Opa1 participates in resistance against the tyrosine kinase inhibitor gefitinib in a lung adenocarcinoma cell line. Respiratory profiling revealed that oxidative metabolism was increased in this gefitinib-resistant lung cancer cell line. Accordingly, resistant cells depended on mitochondrial ATP generation, and their mitochondria were elongated with narrower cristae. In the resistant cells, levels of Opa1 were increased and its genetic or pharmacological inhibition reverted the mitochondrial morphology changes and sensitized them to gefitinib-induced cytochrome c release and apoptosis. In vivo, the size of gefitinib-resistant lung orthotopic tumors was reduced when gefitinib was combined with the specific Opa1 inhibitor MYLS22. The combo gefitinib-MYLS22 treatment increased tumor apoptosis and reduced its proliferation. Thus, the mitochondrial protein Opa1 participates in gefitinib resistance and can be targeted to overcome it.

10.1038/s41419-023-05768-2

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Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease

Disease Models & Mechanisms (2020)

Masafumi Noguchi Kana T. Furukawa Mitsuru Morimoto

ABSTRACT Mammalian lungs have the ability to recognize external environments by sensing different compounds in inhaled air. Pulmonary neuroendocrine cells (PNECs) are rare, multi-functional epithelial cells currently garnering attention as intrapulmonary sensors; PNECs can detect hypoxic conditions through chemoreception. Because PNEC overactivation has been reported in patients suffering from respiratory diseases – such as asthma, chronic obstructive pulmonary disease, bronchopulmonary dysplasia and other congenital diseases – an improved understanding of the fundamental characteristics of PNECs is becoming crucial in pulmonary biology and pathology. During the past decade, murine genetics and disease models revealed the involvement of PNECs in lung ventilation dynamics, mechanosensing and the type 2 immune responses. Single-cell RNA sequencing further unveiled heterogeneous gene expression profiles in the PNEC population and revealed that a small number of PNECs undergo reprogramming during regeneration. Aberrant large clusters of PNECs have been observed in neuroendocrine tumors, including small-cell lung cancer (SCLC). Modern innovation of imaging analyses has enabled the discovery of dynamic migratory behaviors of PNECs during airway development, perhaps relating to SCLC malignancy. This Review summarizes the findings from research on PNECs, along with novel knowledge about their function. In addition, it thoroughly addresses the relevant questions concerning the molecular pathology of pulmonary diseases and related therapeutic approaches.

Reprogramming

Bronchopulmonary Dysplasia

10.1242/dmm.046920

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MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling

Cell Metabolism (2025)

Giovanni Rigoni Enrique Calvo Christina Glytsou Marta Carro-Alvarellos Masafumi Noguchi

10.1016/j.cmet.2025.01.017

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