bims-mimbat 2025-05-04 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2025–05–04
seven papers selected by
José Carlos de Lima-Júnior, Washington University

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
Trade-offs between behavioral plasticity and physiological adaptations in mid-day gerbils (Meriones meridianus) in responses to extreme temperatures.
Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
ATP-release pannexin channels are gated by lysophospholipids.
CRAC channel activity pulsates during cytosolic Ca2+ oscillations.
Diet outperforms microbial transplant to drive microbiome recovery in mice.

Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5
EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

  Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI:  https://doi.org/10.1038/s44319-025-00459-9
J Exp Biol. 2025 May 01. pii: jeb.250423. [Epub ahead of print]

Trade-offs between behavioral plasticity and physiological adaptations in mid-day gerbils (Meriones meridianus) in responses to extreme temperatures.

Yang-Yang Guo, Fangyan Liu, Honglei Chang, Songzhao Du, De-Hua Wang.

  Climate change is reshaping the thermal environment of Meriones meridianus habitats in the Mu Us Desert in China. However, the trade-off between behavioral plasticity and physiological adaptations in this species when coping with extreme temperatures across seasons remains poorly understood. Here, we measured activity patterns and serum and brown adipose tissue (BAT) metabolite levels in this rodent during summer and autumn, and analyzed their relationships with microhabitat temperatures. Behaviorally, 87.9% of extra-burrow summer activity occurred between 22:00-01:00, while autumn activity showed a bimodal distribution: 40.9% concentrated during 18:00-20:00 and 18.9% during 03:00-06:00. This temporal niche shifting effectively minimizes direct heat exposure in summer but provides incomplete protection against autumn cold exposure. Physiologically, serum metabolite concentrations exhibited significant seasonal variations. Specifically, metabolites associated with glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and pathways contributing to acetyl-CoA or TCA cycle intermediates production were downregulated in autumn. Conversely, glycolysis, pyruvate oxidation, the TCA cycle, and oxidative phosphorylation pathways in BAT were significantly enhanced in autumn. Notably, adenosine 5'-triphosphate (ATP) levels in BAT showed no significant seasonal differences. This physiological linkage suggests chronic cold activation of BAT in autumn. Our results show a trade-off where behavioral thermoregulation sufficiently counteracts summer heat through temporal niche shifting but fails to mitigate chronic cold exposure in autumn, necessitating physiological adaptations.

Keywords:  Behavioral plasticity; Brown adipose tissue; Energy metabolism; Mid-day gerbil (Meriones meridianus); Physiological adaptation

DOI:  https://doi.org/10.1242/jeb.250423
Nat Metab. 2025 Apr 28.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.

DOI: https://doi.org/10.1038/s42255-025-01289-8
Elife. 2025 May 01. pii: RP107067. [Epub ahead of print]14

ATP-release pannexin channels are gated by lysophospholipids.

Erik Henze, Russell N Burkhardt, Bennett William Fox, Tyler J Schwertfeger, Eric Gelsleichter, Kevin Michalski, Lydia Kramer, Margret Lenfest, Jordyn M Boesch, Hening Lin, Frank C Schroeder, Toshimitsu Kawate.

  In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.

Keywords:  human; inflammasome; large pore channel; lipid signaling; molecular biophysics; secretomics; structural biology; untargeted metabolomics; xenopus

DOI:  https://doi.org/10.7554/eLife.107067
J Biol Chem. 2025 Apr 23. pii: S0021-9258(25)00368-0. [Epub ahead of print] 108519

CRAC channel activity pulsates during cytosolic Ca2+ oscillations.

Yu-Ping Lin, Erica Scappini, Gary Mirams, Charles J Tucker, Anant B Parekh.

  Intracellular Ca2+ ions are used as second messengers throughout the phylogenetic tree. They are indispensable for diverse biological processes ranging from fertilization to cell death. In Metazoans, signaling information is conveyed via the amplitude, frequency and spatial profile of cytosolic Ca2+ oscillations. In non-excitable cells, these oscillations generally arise from regenerative release of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive intracellular stores, which are refilled by entry of Ca2+ through Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane. However, the precise contribution of these store-operated CRAC channels to Ca2+ oscillations has remained controversial for decades. One view proposes that CRAC channels remain open throughout stimulation, functioning as the pacemaker in setting Ca2+ oscillation frequency. An alternative hypothesis is that channel activity oscillates in parallel with InsP3-driven regenerative Ca2+ release. Here, by tethering a genetically encoded Ca2+ indicator to the pore- forming subunit of the CRAC channel, Orai1, we distinguish between these hypotheses and demonstrate that CRAC channel activity fluctuates in phase with cytosolic Ca2+ oscillations during physiological levels of stimulation. We also find that spatially distinct CRAC channel clusters fire in a coordinated manner, revealing that CRAC channels are not independent units but might function in a synchronized manner to provide pulses of Ca2+ signal at the same time.

Keywords:  Ca(2+) oscillations; Ca(2+) signaling; Orai1; ion channels; receptors

DOI:  https://doi.org/10.1016/j.jbc.2025.108519
Nature. 2025 Apr 30.

Diet outperforms microbial transplant to drive microbiome recovery in mice.

M S Kennedy, A Freiburger, M Cooper, K Beilsmith, M L St George, M Kalski, C Cham, A Guzzetta, S C Ng, F K Chan, O DeLeon, D Rubin, C S Henry, J Bergelson, E B Chang.

A high-fat, low-fibre Western-style diet (WD) induces microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth1,2, which in turn increases risk for a wide array of metabolic3-5, immune6 and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations such as antibiotic treatment7,8, although little is known about the mechanism of impairment and the specific consequences for the host of prolonged post-antibiotic dysbiosis. Here we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) or WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modelling indicates that a RC diet promotes the development of syntrophic cross-feeding interactions, whereas in mice on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for faecal microbiota transplant (FMT) as a strategy to address dysbiosis, and demonstrate that specific dietary interventions are, at a minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural and less invasive alternative.

DOI: https://doi.org/10.1038/s41586-025-08937-9