bims-mimbat 2024-08-18 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024–08–18
thirteen papers selected by
José Carlos de Lima-Júnior, Washington University

Brown adipose tissue facilitates the fever response following infection with Salmonella enterica serovar Typhimurium in mice.
Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.
OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
Timing of acute cold exposure determines UCP1 and FGF21 expression - Possible interactions between the thermal environment, thermoregulatory responses, and peripheral clocks.
Hypoxia decreases mitochondrial ROS production in cells.
Proton gradient across the chloroplast thylakoid membrane governs the redox regulatory function of ATP synthase.
The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice.
Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model.
Mitochondrial complex I promotes kidney cancer metastasis.
Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues.
Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes.
Regulation of mitochondrial metabolism by hibernating bear serum: Insights into seasonal metabolic adaptations.

J Lipid Res. 2024 Aug 09. pii: S0022-2275(24)00122-6. [Epub ahead of print] 100617

Brown adipose tissue facilitates the fever response following infection with Salmonella enterica serovar Typhimurium in mice.

Mohan Li, Marina Barros-Pinkelnig, Günter Weiss, Patrick C N Rensen, Sander Kooijman.

   INTRODUCTION: Brown adipose tissue (BAT) combusts lipids and glucose to generate heat. Via this process of non-shivering thermogenesis, BAT plays a pivotal role in thermoregulation in cold environments, but its contribution to immune-induced fever is less clear.
METHODS: Male APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, and wildtype mice were given an intraperitoneal injection of Salmonella enterica serovar Typhimurium (S.tm). Energy expenditure and substrate utilization, plasma lipid levels, fatty acid uptake by adipose tissues, and lipid content and thermogenic markers in adipose tissues were examined.
RESULTS: S.tm infection led to a set of characteristic symptoms, including elevated body temperature and decreased body weight. Whole-body energy expenditure was significantly decreased 72 hours post-infection, but fat oxidation was increased and accompanied by a substantial reduction in plasma triglyceride (TG) levels as demonstrated in APOE*3-Leiden.CETP mice. S.tm infection strongly increased uptake of fatty acids from TG-rich lipoproteins (TRLs) by BAT, which showed a positive correlation with body temperature in infected mice. Upon histological examination of BAT from wildtype or APOE*3-Leiden.CETP mice, elevated levels of tyrosine hydroxylase were observed, indicative of stimulated sympathetic activity. In addition, the gene expression profile was consistent with more adrenergic stimulation, while lipid content was reduced. Furthermore, browning of white adipose tissue was observed, evidenced by a modest increase in TG-derived fatty acid uptake, the presence of multilocular cells, and induction of UCP-1 expression.
CONCLUSION: We proposed that BAT, or thermogenic adipose tissue in general, is involved in the maintenance of elevated body temperature upon invasive bacterial infection.

Keywords:  Bacterial infection; Brown fat; Fever; Lipoprotein metabolism; Non-shivering thermogenesis

DOI:  https://doi.org/10.1016/j.jlr.2024.100617
J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):

Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.

Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

DOI: https://doi.org/10.1083/jcb.202307036
Am J Physiol Endocrinol Metab. 2024 Aug 14.

Maintenance of thermogenic adipose tissues despite loss of the H3K27 acetyltransferases p300 or CBP.

Daniel Gamu, Makenna S Cameron, William T Gibson.

  Brown and beige adipose tissues are specialized for thermogenesis and are important for energy balance in mice. Mounting evidence suggests chromatin modifying enzymes are integral for the development, maintenance, and functioning of thermogenic adipocytes. p300 and CREB-binding protein (CBP) are histone acetyltransferases (HATs) responsible for writing the transcriptionally activating mark H3K27ac. Despite their homology, p300 and CBP do have unique tissue and context-dependent roles, which have yet to be examined in brown and beige adipocytes specifically. We assessed the requirement of p300 or CBP in thermogenic fat using Ucp1-Cre mediated knockdown in mice to determine if their loss impacted tissue development, susceptibility to diet-induced obesity, and response to pharmacological induction via b3-agonism. Despite successful knockdown, brown adipose tissue mass and expression of thermogenic markers were unaffected by loss of either HAT. As such, knockout mice developed a comparable degree of diet-induced obesity and glucose intolerance to that of floxed controls. Furthermore, "browning" of white adipose tissue by the b3-adrenergic agonist CL-316,243remained largely intact in knockout mice. Although p300 and CBP have non-overlapping roles in other tissues, our results indicate they are individually dispensable within thermogenic fats specifically, possibly due to functional compensation by one another.

Keywords:  brown adipose; histone acetyltransferases; metabolism; obesity; thermogenesis

DOI:  https://doi.org/10.1152/ajpendo.00120.2024
Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]

OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.

Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.

  Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.

Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT

DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
J Therm Biol. 2024 Aug 10. pii: S0306-4565(24)00156-6. [Epub ahead of print]124 103938

Timing of acute cold exposure determines UCP1 and FGF21 expression - Possible interactions between the thermal environment, thermoregulatory responses, and peripheral clocks.

Phong Kt Chau, Elin Ryan, Knut Tomas Dalen, Fred Haugen.

Thermoregulation is synchronized across the circadian cycle to uphold thermal homeostasis. To test if time-of-day matters for the response to environmental cold exposure, mice were acclimated to thermoneutrality (27 °C) for 2 months were subjected acutely (8 h) to cold ambient conditions (15 °C), whereas controls were maintained at thermoneutral conditions. The thermal exposure was tested in separate groups (N = 8) at three distinct time-of-day periods: in the LIGHT phase (L); the DARK phase (D); and a mix of the two (D + L). The magnitude of UCP1 protein and mRNA induction in brown adipose tissue (BAT) in response to acute cold exposure was time-of-day sensitive, peaking in LIGHT, whereas lower induction levels were observed in D + L, and DARK. Plasma levels of FGF21 were induced 3-fold by acute cold exposure at LIGHT and D + L, compared to the time-matched thermoneutral controls, whereas cold in DARK did not cause a significant increase of FGF21 plasma levels. Cold exposure affected, in BAT, the temporal mRNA expression patterns of core circadian clock components: Bmal1, Clock, Per1, Per3, Cry1, Cry2 Nr1d1, and Nr1d2, but in the liver, none of the transcripts were modified. Behavioral assessment using the Thermal Gradient Test (TGT) showed that acute cold exposure reduced cold sensitivity in D + L, but not in DARK. RNA-seq analyses of somatosensory neurons in DRG highlighted the role of the core circadian components in these cells, as well as transcriptional changes due to acute cold exposure. This elucidates the sensory system as a gauge and potential regulator of thermoregulatory responses based on circadian physiology. In conclusion, acute cold exposure elicits time-of-day specific effects on thermoregulatory pathways, which may involve underlying changes in thermal perception. These results have implications for efforts aimed at reducing risks associated with the organization of shift work in cold environments.

DOI: https://doi.org/10.1016/j.jtherbio.2024.103938
Free Radic Biol Med. 2024 Aug 13. pii: S0891-5849(24)00603-8. [Epub ahead of print]224 1-8

Hypoxia decreases mitochondrial ROS production in cells.

Bijoya Sen, Bérengère Benoit, Martin D Brand.

  We re-examined the reported increase in mitochondrial ROS production during acute hypoxia in cells. Using the Amplex Ultrared/horseradish peroxidase assay we found a decrease, not increase, in hydrogen peroxide release from HEK293 cells under acute hypoxia, at times ranging from 1 min to 3 h. The rates of superoxide/hydrogen peroxide production from each of the three major sites (site IQ in complex I and site IIIQo in complex III in mitochondria, and NADH oxidases (NOX) in the cytosol) were decreased to the same extent by acute hypoxia, with no change in the cells' ability to degrade added hydrogen peroxide. A similar decrease in ROS production under acute hypoxia was found using the diacetyldichlorofluorescein assay. Using a HIF1α reporter cell line we confirmed earlier observations that suppression of superoxide production by site IIIQo decreases HIF1α expression, and found similar effects of suppressing site IQ or NOX. We conclude that increased mitochondrial ROS do not drive the response of HIF1α to acute hypoxia, but suggest that cytosolic H2O2 derived from site IQ, site IIIQo and NOX in cells is necessary to permit HIF1α stabilization by other signals.

Keywords:  HEK293; HIF1α; Hydrogen peroxide; NOX; Oxygen concentration; Reactive oxygen species; S1QEL; S3QEL; Superoxide

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.016
J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02160-4. [Epub ahead of print] 107659

Proton gradient across the chloroplast thylakoid membrane governs the redox regulatory function of ATP synthase.

Takatoshi Sekiguchi, Keisuke Yoshida, Ken-Ichi Wakabayashi, Toru Hisabori.

  Chloroplast ATP synthase (CFoCF1) synthesizes ATP by using a proton electrochemical gradient across the thylakoid membrane, termed ΔμH+, as an energy source. This gradient is necessary not only for ATP synthesis but also for reductive activation of CFoCF1 by thioredoxin, using reducing equivalents produced by the photosynthetic electron transport chain. ΔμH+ comprises two thermodynamic components: pH differences across the membrane (ΔpH) and the transmembrane electrical potential (ΔΨ). In chloroplasts, the ratio of these two components in ΔμH+ is crucial for efficient solar energy utilization. However, the specific contribution of each component to the reductive activation of CFoCF1 remains unclear. In this study, an in vitro assay system for evaluating thioredoxin-mediated CFoCF1 reduction is established, allowing manipulation of ΔμH+ components in isolated thylakoid membranes using specific chemicals. Our biochemical analyses revealed that ΔpH formation is essential for thioredoxin-mediated CFoCF1 reduction on the thylakoid membrane, whereas ΔΨ formation is nonessential.

Keywords:  Chloroplast ATP synthase; proton electrochemical gradient; redox regulation; thioredoxin

DOI:  https://doi.org/10.1016/j.jbc.2024.107659
Mol Metab. 2024 Aug 11. pii: S2212-8778(24)00136-4. [Epub ahead of print] 102005

The mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice.

Christopher E Shannon, Terry Bakewell, Marcel J Fourcaudot, Iriscilla Ayala, Annie A Smelter, Edgar A Hinostroza, Giovanna Romero, Mara Asmis, Leandro C Freitas Lima, Martina Wallace, Luke Norton.

   OBJECTIVE: The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.
METHODS: The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.
RESULTS: Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1AD-/- mice regardless of sex, even under conditions of zero dietary fat.
CONCLUSION: These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.

Keywords:  Adipose; glyceroneogenesis; lipogenesis; mitochondria; sexual dimorphism

DOI:  https://doi.org/10.1016/j.molmet.2024.102005
Cardiovasc Diabetol. 2024 Aug 14. 23(1): 298

Identification of regulatory networks and crosstalk factors in brown adipose tissue and liver of a cold-exposed cardiometabolic mouse model.

Melina Amor, Malena Diaz, Valentina Bianco, Monika Svecla, Birgit Schwarz, Silvia Rainer, Anita Pirchheim, Laszlo Schooltink, Suravi Mukherjee, Gernot F Grabner, Giangiacomo Beretta, Claudia Lamina, Giuseppe Danilo Norata, Hubert Hackl, Dagmar Kratky.

   BACKGROUND: Activation of brown adipose tissue (BAT) has gained attention due to its ability to dissipate energy and counteract cardiometabolic diseases (CMDs).
METHODS: This study investigated the consequences of cold exposure on the BAT and liver proteomes of an established CMD mouse model based on LDL receptor-deficient (LdlrKO) mice fed a high-fat, high-sucrose, high-cholesterol diet for 16 weeks. We analyzed energy metabolism in vivo and performed untargeted proteomics on BAT and liver of LdlrKO mice maintained at 22 °C or 5 °C for 7 days.
RESULTS: We identified several dysregulated pathways, miRNAs, and transcription factors in BAT and liver of cold-exposed Ldlrko mice that have not been previously described in this context. Networks of regulatory interactions based on shared downstream targets and analysis of ligand-receptor pairs identified fibrinogen alpha chain (FGA) and fibronectin 1 (FN1) as potential crosstalk factors between BAT and liver in response to cold exposure. Importantly, genetic variations in the genes encoding FGA and FN1 have been associated with cardiometabolic-related phenotypes and traits in humans.
DISCUSSION: This study describes the key factors, pathways, and regulatory networks involved in the crosstalk between BAT and the liver in a cold-exposed CMD mouse model. These findings may provide a basis for future studies aimed at testing whether molecular mediators, as well as regulatory and signaling mechanisms involved in tissue adaption upon cold exposure, could represent a target in cardiometabolic disorders.

Keywords:  Brown adipose tissue; Cardiometabolic diseases; Cold exposure; Ldlr-deficient mice; Liver; Untargeted proteomics

DOI:  https://doi.org/10.1186/s12933-024-02397-7
Nature. 2024 Aug 14.

Mitochondrial complex I promotes kidney cancer metastasis.

Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

DOI: https://doi.org/10.1038/s41586-024-07812-3
bioRxiv. 2024 Jul 31. pii: 2024.07.30.605812. [Epub ahead of print]

Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues.

Xiao Zhang, Anurag Majumdar, Clara Kim, Brian Kleiboeker, Kristann L Magee, Brian S Learman, Steven A Thomas, Irfan J Lodhi, Ormond A MacDougald, Erica L Scheller.

Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

DOI: https://doi.org/10.1101/2024.07.30.605812
bioRxiv. 2024 Jul 31. pii: 2024.07.30.605923. [Epub ahead of print]

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes.

Grace Z Yu, Nicole A J Krentz, Liz Bentley, Meng Zhao, Keanu Paphiti, Han Sun, Julius Honecker, Marcus Nygård, Hesam Dashti, Ying Bai, Madeleine Reid, Swaraj Thaman, Martin Wabitsch, Varsha Rajesh, Jing Yang, Katia K Mattis, Fernando Abaitua, Ramon Casero, Hans Hauner, Joshua W Knowles, Joy Y Wu, Susanne Mandrup, Melina Claussnitzer, Katrin J Svensson, Roger D Cox, Anna L Gloyn.

  There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1 +/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1 +/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

Keywords:  Diabetes; RREB1; adipocyte; insulin sensitivity; transcription factor

DOI:  https://doi.org/10.1101/2024.07.30.605923
Biochem Biophys Res Commun. 2024 Aug 05. pii: S0006-291X(24)01046-5. [Epub ahead of print]736 150510

Regulation of mitochondrial metabolism by hibernating bear serum: Insights into seasonal metabolic adaptations.

Mohamed Elfeky, Ayumi Tsubota, Michito Shimozuru, Toshio Tsubota, Kazuhiro Kimura, Yuko Okamatsu-Ogura.

  Hibernating animals undergo a unique and reversible decrease in their whole-body metabolism, which is often accompanied by a suppression of mitochondrial respiration. However, the precise mechanisms underlying these seasonal shifts in mitochondrial metabolism remain unclear. In this study, the effect of the serum from active and hibernating Japanese black bears on mitochondrial respiration was assessed. Stromal-vascular cells were obtained from bear white adipose tissue and cultured with or without an adipocyte differentiation cocktail. When the oxygen consumption was measured in the presence of bear serum, the hibernating bear serum reduced maximal respiration by 15.5 % (p < 0.05) and spare respiratory capacity by 46.0 % (p < 0.01) in the differentiated adipocytes in comparison to the active bear serum. Similar reductions of 23.4 % (p = 0.06) and 40.6 % (p < 0.05) respectively were observed in undifferentiated cells, indicating the effect is cell type-independent. Blue native PAGE analysis revealed that hibernating bear serum suppressed cellular metabolism independently of the assembly of mitochondrial respiratory chain complexes. RNA-seq analysis identified 1094 differentially expressed genes (fold change>1.5, FDR<0.05) related to insulin signaling and glucose metabolism pathways. These findings suggest that the rapid alterations in mitochondrial metabolism during hibernation are likely induced by a combination of reduced insulin signaling and suppressed mitochondrial function, rather than changes in respiratory complex assembly.

Keywords:  Hibernation; Japanese black bears; Mitochondrial metabolism; Respiratory chain complexes

DOI:  https://doi.org/10.1016/j.bbrc.2024.150510