bims-mimbat 2025-02-16 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2025–02–16
six papers selected by
José Carlos de Lima-Júnior, Washington University

Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice.
The wintertime brown adipose tissue thermogenesis of New York City residents amidst climate change.
Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype.
Mitochondrial potassium channels: New properties and functions.
Mechanistic insights into inactivating mutations in the proton-coupled folate transporter (SLC46A1), and compensatory mutations that restore function.

J Biol Chem. 2025 Feb 11. pii: S0021-9258(25)00141-3. [Epub ahead of print] 108293

Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice.

Meng Zou, Katsuya Tanabe, Kikuko Amo-Shiinoki, Daisuke Kohno, Syota Kagawa, Hideki Shirasawa, Kenji Ikeda, Akihiko Taguchi, Yasuharu Ohta, Shigeru Okuya, Tetsuya Yamada, Tadahiro Kitamura, Hiroshi Masutani, Yukio Tanizawa.

  Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining non-shivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30°C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5°C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16°C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.

Keywords:  Thioredoxin-interacting protein; brown adipose tissue; cold stress; metabolism; thermogenesis

DOI:  https://doi.org/10.1016/j.jbc.2025.108293
Ann Hum Biol. 2025 Dec;52(1): 2455685

The wintertime brown adipose tissue thermogenesis of New York City residents amidst climate change.

Stephanie B Levy, Shelby Pirtle, Ruthbernick Bastien, Kandra Cruz, Jahnae Vernon.

   BACKGROUND: The built environment buffers residents of large cities, such as New York (NYC), from exposure to low temperatures. Furthermore, average winter temperatures are rising in NYC due to climate change. The degree to which NYC residents exhibit metabolic adaptations to cold stress is currently unclear.
AIM: This study quantified variation in brown adipose tissue (BAT), energy expenditure (EE), and ambient temperature among NYC residents.
SUBJECTS AND METHODS: We recruited 46 adults (31 females; 15 males) and quantified anthropometrics, change in EE, and BAT thermogenesis after a cooling condition in the lab. A subsample of 21 participants wore temperature loggers for three days in order to quantify ambient temperature exposure.
RESULTS: BAT thermogenesis was not significantly associated with change in EE. Participants that were exposed to lower average temperatures exhibited greater BAT thermogenesis (p = 0.013). Change in EE, however, was not significantly associated with time spent outside nor average temperature exposure.
CONCLUSION: Our study provides mixed evidence for the role of BAT thermogenesis in metabolic adaptations to cold stress among NYC residents. Many young adults in NYC are exposed to minimal amounts of cold stress, and this trend is likely to be exacerbated by climate change.

Keywords:  Metabolism; adaptation; cold stress; urban environments

DOI:  https://doi.org/10.1080/03014460.2025.2455685
Elife. 2025 Feb 12. pii: RP100541. [Epub ahead of print]13

Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.

Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prerona Bora, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy E Shutt, Danielle A Grotjahn, R Luke Wiseman.

  Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

Keywords:  cell biology; human; integrated stress response; mitochondrial fragmentation; mitochondrial morphology; mouse; stress signaling

DOI:  https://doi.org/10.7554/eLife.100541
FASEB J. 2025 Feb 15. 39(3): e70389

CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype.

Júlia Z Castelli, Helena F Raposo, Claudia D C Navarro, Carolina M Lazaro, Marina R Sartori, Ana Paula Dalla Costa, Pedro A S Nogueira, Lício A Velloso, Anibal E Vercesi, Helena C F Oliveira.

  Susceptibility to obesity differs depending on the genetic background and housing temperatures. We have recently reported that CETP expressing female mice are leaner due to increased lipolysis, brown adipose tissue (BAT) activity, and body energy expenditure compared to nontransgenic (NTg) littermates under standard housing temperature (22°C). The aim of this study is to evaluate how CETP expression affects body temperature, composition, and metabolism during cold exposure (4°C) and thermoneutrality (30°C). When submitted to cold, CETP mice maintained rectal temperature, body weight, and food intake similarly to NTg mice along acute or chronic exposure to 4°C. The body oxygen consumption in response to an isoproterenol challenge was 21% higher at 22°C, and 41% higher after 7 days of cold exposure in CETP than in NTg mice. In addition, BAT biopsies from CETP mice showed reduced lipid content and increased basal oxygen consumption rates. Under thermoneutrality (30°C), when BAT activity is inhibited, CETP mice showed higher rectal and tail temperatures, increased food intake, and increased energy expenditure. Lean mass was elevated and fat mass reduced in CETP mice kept at 30°C. In this thermoneutral condition, soleus muscle, but not gastrocnemius or liver of CETP mice, showed increased mitochondrial respiration rates. These data indicate that CETP expression confers a greater capacity of elevating body metabolic rates at both cold exposure, through BAT activity, and at thermoneutrality, through increased muscle metabolism. Thus, the CETP expression levels in females should be considered as a new influence in the contexts of obesity and metabolic disorders propensity.

Keywords:  CETP; RRID:IMSR_JAX:001929; RRID:IMSR_JAX:003904; RRID:MGI:7264953; body metabolic rate; brown adipose tissue; cold exposure; respiration; thermoneutrality

DOI:  https://doi.org/10.1096/fj.202402843RR
Biochim Biophys Acta Bioenerg. 2025 Feb 09. pii: S0005-2728(25)00012-X. [Epub ahead of print] 149546

Mitochondrial potassium channels: New properties and functions.

Adam Szewczyk, Piotr Bednarczyk, Bogusz Kulawiak, Monika Żochowska, Barbara Kalenik, Joanna Lewandowska, Karolina Pytlak, Shur Gałecka, Antoni Wrzosek, Piotr Koprowski.

  Mitochondria are recently implicated in phenomena such as cytoprotection, cellular senescence, tumor metabolism, and inflammation. The basis of these processes relies on biochemical functions of mitochondria such as the synthesis of reactive oxygen species or biophysical properties such as the integrity of the inner mitochondrial membrane. The transport of potassium cations plays an important role in all these events. The K+ influx is mediated by potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of our new findings on the properties of mitochondrial large-conductance calcium-activated and mitochondrial ATP-regulated potassium channels. This concerns the role of mitochondrial potassium channels in cellular senescence, and interactions with other mitochondrial proteins or small molecules such as quercetin, hemin, and hydrogen sulfide. We also discuss the prospects of research on potassium channels present in mitochondria.

Keywords:  Hemin; Hydrogen sulfide; Kinases; Mitochondria; Potassium channels; Quercetin; ROS; Senescence

DOI:  https://doi.org/10.1016/j.bbabio.2025.149546
J Biol Chem. 2025 Feb 07. pii: S0021-9258(25)00128-0. [Epub ahead of print] 108280

Mechanistic insights into inactivating mutations in the proton-coupled folate transporter (SLC46A1), and compensatory mutations that restore function.

Prithviraj Nandigrami, I David Goldman, Andras Fiser.

Hereditary folate malabsorption (HFM) is a rare, autosomal recessive disorder characterized by impaired intestinal absorption and impaired transport of folates across the choroid plexus into cerebral spinal fluid due to inactivating mutations in the hPCFT gene, which encodes the proton-coupled folate transporter (PCFT-SLC46A1). Understanding the structural impact of these mutations is crucial for elucidating the mechanistic basis for PCFT function and the pathophysiology of HFM. Recently, the cryo-electron microscopic structural characterization of the Gallus gallus PCFT (gPCFT) was obtained, which shares significant sequence identity with hPCFT. We conducted molecular dynamics (MD) simulations of human PCFT (hPCFT) based on this structure, to explore structural changes induced by functionally defective disease-causing and other mutant proteins and mutations that restore function. Simulations revealed that the mutually mechanistic basis for the loss of function is partial loss of structural integrity of hPCFT primarily manifested in an enlarged and distorted pore accompanied by loss of long-range contacts, less stable, fluctuating inner helices with reduced solvent accessibility and a marked loss of ordered secondary structures. These changes are reversed by the introduction of compensatory mutations. These findings provide novel insights into the structural and functional consequences of PCFT mutations associated with HFM and provide correlations with kinetic and biochemical properties of the mutant proteins.

DOI: https://doi.org/10.1016/j.jbc.2025.108280