bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–06–15
five papers selected by
José Carlos de Lima-Júnior, Washington University



  1. Mol Metab. 2025 Jun 09. pii: S2212-8778(25)00091-2. [Epub ahead of print] 102184
       OBJECTIVES: Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors involved in the control of lipid metabolism. The PPARα isoform is highly expressed in brown adipose tissue (BAT). However, its precise role in BAT remains unclear. Here, we aimed to investigate the role of PPARα in BAT of high fat diet-induced obese mice in a thermoneutral environment.
    METHODS: We used tamoxifen-inducible-BAT specific PPARα knockout mice (PPARαBATKO) that were housed at thermoneutrality to minimize BAT basal activation, fed a high-fat diet for 20 weeks and challenged with a β3-adrenergic agonist (CL316,243) during the last week. Both male and female mice were studied.
    RESULTS: Body weight and glucose tolerance tests were similar in both sexes and genotypes. However, BAT morphology was altered in PPARαBATKO mice, with more unilocular and larger lipid droplets compared to control mice, suggesting BAT impaired function. Indeed, when treated with CL316,243, both male and female mice had increased de novo lipogenesis (DNL), reflected by an increased expression of ChREBPβ and lipogenic enzymes ACLY, ACC1, FASN and SCD1. These changes were accompanied by an increase in fatty acids in triglycerides, and thus an increase in lipid storage. Moreover, lipid profiles in phospholipids were different, suggesting a modification in the membrane content with an increase of palmitoleate.
    CONCLUSIONS: Altogether, our results reveal a key role for PPARα in DNL in BAT and in the regulation of lipid metabolism in HFD-induced obesity.
    Keywords:  Peroxisome Proliferator-Activated Receptor alpha; brown adipose tissue; high fat diet-induced obesity; inducible UCP1-CRE; lipid metabolism; β(3)-adrenergic stimulation
    DOI:  https://doi.org/10.1016/j.molmet.2025.102184
  2. Acta Physiol (Oxf). 2025 Jul;241(7): e70068
       BACKGROUND: Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism.
    METHODS: We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis.
    RESULTS: We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein-lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2-H3 and H4-H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein-lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane.
    CONCLUSION: We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.
    Keywords:  anion transporter; cardiolipin; fatty acid cycling; mitochondrial SLC25 family; molecular dynamics simulations; proton transport mechanism
    DOI:  https://doi.org/10.1111/apha.70068
  3. Nature. 2025 Jun 11.
      Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41586-025-09162-0
  4. Nature. 2025 Jun 11.
      Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09097-6
  5. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020