Biology subjects

Kajimura, S.

Publications and source records attributed to Kajimura, S..

15 recordsLinked to original sources

bioRxiv2026

A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation

Temperature is a fundamental determinant of mammalian metabolism. The canonical cold-adaptation pathway involves cold sensing by peripheral sensory neurons, which activate sympathetic outflow, {beta}-adrenergic signaling, and lipolysis in adipose tissue. In contrast, we report here a cell-intrinsic mechanism by which physiologically relevant cooling temperatures (27-31 oC) enhance lipolysis in subcutaneous adipose tissue. Mechanistically, cooling drives liquid-liquid phase separation (LLPS) of perilipin 1 (PLIN1), the dominant lipid droplet coat protein, promoting its condensation and the local recruitment of PKA to the droplet surface. This spatial reorganization selectively amplified PKA-mediated perilipin 1 phosphorylation, CGI-58 release, and ATGL-dependent lipolysis. The process depends on the intrinsically disordered region (IDR) of perilipin1, where four aromatic residues, conserved in endotherms but not in ectotherms, are required for cooling-induced LLPS and lipolysis in vivo. Notably, targeted delivery of an LLPS-competent perilipin 1 variant to the inguinal adipose tissue of mice enhanced local lipolysis and reduced depot mass. Together, these findings uncover a cell-intrinsic thermosensitive mechanism that can tune lipolytic responsiveness, offering a possible strategy for targeted depot-selective fat reduction.

cell biology↗

bioRxiv2026

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress. TeaserMitochondrial metabolite transport is tailored to meet muscle-specific needs for utilizing amino acids during fasting.

physiology↗

bioRxiv2026

BAT protects against hepatic oxidative stress by remodeling the circulating metabolome

Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.

physiology↗

bioRxiv2026

Identity-state expression and switching in co-conscious dissociative identity disorder: a non-traumatic proof-of-concept fMRI study

Dissociative identity disorder (DID) remains debated because identity-state phenomena are privately experienced and may be attributed to suggestion, simulation or role enactment. Most neuroimaging studies rely on symptom provocation or traumatic recall, which complicates interpretation and is poorly suited to co-conscious presentations where simultaneous awareness should make state differences hardest to detect. We applied Identity-State Characterization and Analysis (ID-SCAN), a non-traumatic, identity-cued functional magnetic resonance imaging protocol, to a DSM-5-diagnosed woman with persistent co-consciousness between Adult and Adolescent identity-states. One task used identical insect images that evoked opposite preferences across identity-states; the other used trait judgments about self, the other identity-state and a shared intimate other. Analyses combined Bayesian single-case general linear modelling, generalized psychophysiological interaction connectivity and searchlight representational similarity analysis. Identity-instruction cue epochs were pooled across tasks to assess switch direction. The same insect stimuli engaged different valuation-related configurations across identity-states: Adolescent-selective effects centred on striato-thalamic regions, whereas Adult-selective effects extended to amygdala and orbitofrontal/medial prefrontal cortex, with distinct task-evoked coupling. Adult-as-self and Adolescent-as-self occupied separable positions within canonical self-referential regions. Cue-locked activity differed by switch direction across tasks, with larger reconfiguration when switching to Adult (mean between-cluster beta separation 4.30 versus 0.85; permutation p = 0.0001). Cross-task overlap localized a limited shared task-related substrate mainly to posterior visual and dorsal parietal cortex. Even under persistent co-consciousness and without trauma provocation, identity-state expression and switching showed convergent within-person neural signatures. The findings support non-traumatic mechanistic phenotyping of dissociative presentations and motivate cohort and longitudinal studies, including treatment-tracking work.

neuroscience↗

bioRxiv2025

Mitochondrial control of fuel switching via carnitine biosynthesis

Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.

biochemistry↗

bioRxiv2025

Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35

Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.

cell biology↗

bioRxiv2024

ZIP13 regulates lipid metabolism by changing intracellular iron and zinc balance

Metabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits the adipocyte browning pathway by modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates the homeostasis of adipose tissue remain unclear and therefore, we investigated the role of ZIP13 in mature adipocytes using adipocyte-specific Zip13-deficient mice. We herein demonstrate that these mice show accelerated lipolysis and reduced respiratory exchange ratio. In addition, abundance of iron and zinc balance were altered during differentiation in normal adipocytes, whereas iron distribution was substantially affected in Zip13-deficient adipocytes, which downregulated PDE activity and enhanced {beta}-adrenergic receptor signaling pathways. Importantly, we confirmed that ZIP13 could transport both zinc and iron, using the Xenopus oocyte transport system and in silico structural dynamics simulations, and that the defect in iron distribution perturbs proper lipolysis. Together, these results illustrate that ZIP13 acts as a key regulator for lipolysis in adipocytes via the proper use of metals, and that the ZIP13-iron axis plays an important role in regulation of lipid metabolism.

cell biology↗

bioRxiv2024

Sympathetic neuron-derived NPY protects from obesity by sustaining the mural progenitors of thermogenic adipocytes.

Neuropeptide Y (NPY) is secreted by sympathetic nerves1,2, but its direct impact on thermogenic adipocytes is unknown. Here we uncover the mechanism by which peripheral NPY protects from obesity. Our imaging of cleared murine brown and white adipose tissue (BAT and WAT) established that NPY+ sympathetic axons are only a minority that mostly maps to the peri-vasculature; our analysis of single-cell RNA-sequencing datasets identifies mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains mural cells, which are known to be a source of beige cells in both BAT and WAT3-5 and that NPY facilitates the differentiation to thermogenic adipocytes. We found that diet-induced-obesity leads to neuropathy of NPY+ axons and concomitant depletion of the mural cell pool of beige fat progenitors. This defect is replicated in conditional knockout (cKO) mice with NPY specifically abrogated from sympathetic neurons. These cKO mice have whitened BAT with reduced thermogenic ability and lower energy expenditure even before the onset of obesity; they develop adult-onset obesity on a regular chow diet and are more susceptible to diet induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by the sympathetic nerves has the opposite effect on body weight homeostasis by sustaining the proliferation of the mural cell progenitors of thermogenic adipocytes.

physiology↗

bioRxiv2024

Mitochondrial choline import regulates purine nucleotide pools via SLC25A48

Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo. We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival. Key pointsO_LISLC25A48 is required for mitochondrial choline uptake. C_LIO_LIMitochondrial choline uptake regulates one-carbon contribution to purine nucleotide synthesis. C_LIO_LIBrown fat thermogenesis requires mitochondrial choline catabolism for respiratory capacity. C_LIO_LICancer cells require mitochondrial choline uptake for cell survival. C_LI

cell biology↗

bioRxiv2022

A liver-specific mitochondrial carrier that controls gluconeogenesis and energy expenditure

Mitochondria provide essential metabolites and ATP for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report a liver-specific mitochondrial inner-membrane carrier, SLC25A47, which is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific deletion of Slc25a47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 deletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 loss leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the mitochondrial inner-membrane that regulates fasting-induced gluconeogenesis and energy homeostasis. SIGNIFICANCEGiven the impenetrable nature of the mitochondrial inner-membrane, most of the known metabolite carrier proteins, including SLC25A family members, are ubiquitously expressed in mammalian tissues. One exception is SLC25A47 which is selectively expressed in the liver. The present study showed that depletion of SLC25A47 reduced mitochondrial pyruvate flux and hepatic gluconeogenesis under a fasted state, while activating energy expenditure. The present work offers a liver-specific target through which we can restrict hepatic gluconeogenesis, which is often in excess under hyperglycemic and diabetic conditions.

physiology↗

bioRxiv2022

Interleukin-17 drives sex-dependent weight loss and changes in feeding behaviour during Trypanosoma brucei infection

In the skin, Trypanosoma brucei colonises the subcutaneous white adipose tissue (scWAT) and harbours a pool of parasites that are proposed to be competent for forward transmission. The interaction between parasites, adipose tissue, and the local immune system is likely to drive the adipose tissue wasting and weight loss observed in cattle and humans infected with T. brucei. However, mechanistically, the events leading to scWAT wasting are not fully understood. Here, using several complementary approaches, including mass cytometry by time of flight, bulk and single cell transcriptomics, and in vivo genetic models, we found that T. brucei infection drives local expansion of several IL-17A-producing cells in the murine WAT, including TH17 and V{gamma}6+ T cells. We also found that global IL-17 deficiency, or mice lacking IL-17 receptor expression exclusively in adipocytes, were protected from infection-induced WAT wasting and weight loss. Unexpectedly, we found that abrogation of IL-17 signalling in adipocytes results in a significant accumulation of Dpp4+ Pi16+ interstitial preadipocytes and a higher burden of extravascular parasites in the WAT, highlighting a critical role for IL-17 signalling in controlling preadipocyte fate, scWAT tissue dynamics, and local parasite burden. Taken together, our study highlights the central role of adipocyte IL-17 signalling in controlling WAT responses to infection, suggesting that adipocytes are a critical coordinator of the tissue dynamics and immune responses to T. brucei infection.

immunology↗

bioRxiv2021

Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever

Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA, Valine, Leucine, and Isoleucine) are essential for anabolic processes like protein synthesis, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.

cell biology↗

bioRxiv2019

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output. Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a mutant heart as a possible consequence of Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1) activation, consistent with a recent intriguing report that CoQ may function as a natural ligand and partial agonist of Peroxisome Proliferator-Activated Receptor (PPAR) /{gamma}. Taken together, our study reveals a previously unknown function of a novel striated muscle-enriched mitochondrial protein Coq10a in regulating postnatal heart growth.

developmental biology↗

bioRxiv2019

Mindfulness meditation changes the boundary and configuration of the primary functional networks in the brain

Research has shown that meditation not only improves our cognitive and motivational functioning (e.g., attention, mental health), it influences the way how our brain networks [e.g., default mode network (DMN), fronto-parietal network (FPN), and sensory-motor network (SMN)] function and operate. However, surprisingly little attention has been paid to the possibility that meditation alters the structure (composition) of these functional brain networks. Here, using a single-case experimental design with longitudinal intensive data, we examined the effect of mediation practice on intra-individual changes in the composition of whole-brain networks. The results showed that meditation (1) changed the community size (with a number of regions in the FPN being merged into the DMN after meditation), (2) changed the brain regions composing the SMN community without changing its size, and (3) led to instability in the community allegiance of the regions in the FPN. These results suggest that, in addition to altering specific functional connectivity, meditation leads to reconfiguration of whole-brain network structure. The reconfiguration of community structure in the brain provides fruitful information about the neural mechanisms of meditation.

neuroscience↗

bioRxiv2018

Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain elusive. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We identify connexin 31 (GJB3), which promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer. One sentence summaryGap junctions between breast cancer cells and adipocytes transfer cAMP and activate lipolysis in the breast tumor microenvironment to support growth.

cancer biology↗