bims-mimbat 2025-03-02 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2025–03–02
eight papers selected by
José Carlos de Lima-Júnior, Washington University

Mitochondrial superoxide regulates pro-inflammatory macrophages.
Temperature-driven trade-off between mitochondrial activity and efficiency in live rotifers representing different thermal histories.
MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes.
Dynamic PRDX S-acylation modulates ROS stress and signaling.
Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.
Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site.

Nat Metab. 2025 Feb 24.

Mitochondrial superoxide regulates pro-inflammatory macrophages.

DOI: https://doi.org/10.1038/s42255-025-01223-y
J Exp Biol. 2025 Feb 24. pii: jeb.249338. [Epub ahead of print]

Temperature-driven trade-off between mitochondrial activity and efficiency in live rotifers representing different thermal histories.

Agata Burzawa, Katarzyna Potera, Eugene P Sokolov, Inna M Sokolova, Aleksandra Walczyńska.

  Mitochondria generate up to 90% of cellular ATP, making it critical to understand how abiotic factors affect mitochondrial function under varying conditions. Using clones of the rotifer Lecane inermis with known thermal preferences, we investigated mitochondrial bioenergetic responses to four thermal regimes: standard temperature, optimal temperature, low suboptimal temperature, and high suboptimal temperature. The study aimed to determine how mitochondrial parameters in intact organisms vary with temperature shifts and whether these responses differ across experimental populations. We assessed key bioenergetic parameters: routine respiration (representing overall metabolic rate), electron transport system (ETS) capacity (indicative of oxidative phosphorylation potential), and proton leak rates (reflecting the energetic costs of maintaining mitochondrial membrane potential). Our results showed that populations with different thermal preferences displayed distinct mitochondrial responses to temperature changes, particularly at suboptimal temperatures. In contrast, responses were more uniform under standard and optimal conditions. Our findings demonstrated that metabolic plasticity in changing environments often involves trade-offs between mitochondrial efficiency and maintenance. By studying mitochondrial respiration at the whole-organism level, we revealed the complex temperature dependence of bioenergetic traits, providing insights beyond isolated mitochondria studies. This research highlights how a cascade of plastic responses spanning from mitochondrial responses to overall growth patterns is triggered by temperature changes, offering a valuable perspective in the context of global warming and organismal adaptation.

Keywords:  ATP turnover; Coupling efficiency; ETS; Mitochondria; Proton leak; Temperature-size rule

DOI:  https://doi.org/10.1242/jeb.249338
Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]

MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.

Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.

  Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.

Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability

DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
Nat Commun. 2025 Feb 27. 16(1): 2044

Kingdom-specific lipid unsaturation calibrates sequence evolution in membrane arm subunits of eukaryotic respiratory complexes.

Pooja Gupta, Sristi Chakroborty, Arun K Rathod, K Ranjith Kumar, Shreya Bhat, Suparna Ghosh, Pallavi Rao T, Kameshwari Yele, Raman Bakthisaran, R Nagaraj, Moutusi Manna, Swasti Raychaudhuri.

Sequence evolution of protein complexes (PCs) is constrained by protein-protein interactions (PPIs). PPI-interfaces are predominantly conserved and hotspots for disease-related mutations. How do lipid-protein interactions (LPIs) constrain sequence evolution of membrane-PCs? We explore Respiratory Complexes (RCs) as a case study as these allow to compare sequence evolution in subunits exposed to both lipids in inner-mitochondrial membrane (IMM) and lipid-free aqueous matrix. We find that lipid-exposed surfaces of the IMM-subunits but not of the matrix subunits are populated with non-PPI disease-causing mutations signifying LPIs in stabilizing RCs. Further, IMM-subunits including their exposed surfaces show high intra-kingdom sequence conservation but remarkably diverge beyond. Molecular Dynamics simulation suggests contrasting LPIs of structurally superimposable but sequence-wise diverged IMM-exposed helices of Complex I (CI) subunit Ndufa1 from human and Arabidopsis depending on kingdom-specific unsaturation of cardiolipin fatty acyl chains. in cellulo assays consolidate inter-kingdom incompatibility of Ndufa1-helices due to the lipid-exposed amino acids. Plant-specific unsaturated fatty acids in human cells also trigger CI-instability. Taken together, we posit that altered LPIs calibrate sequence evolution at the IMM-arms of eukaryotic RCs.

DOI: https://doi.org/10.1038/s41467-025-57295-7
Cell Chem Biol. 2025 Feb 19. pii: S2451-9456(25)00032-7. [Epub ahead of print]

Dynamic PRDX S-acylation modulates ROS stress and signaling.

Tian Qiu, Saara-Anne Azizi, Shubhashree Pani, Bryan C Dickinson.

  Peroxiredoxins (PRDXs) are a highly conserved family of peroxidases that serve as the primary scavengers of peroxides. Post-translational modifications play crucial roles modulating PRDX activities, tuning the balance between reactive oxygen species (ROS) signaling and stress. We previously reported that S-acylation occurs at the "peroxidatic" cysteine (Cp) site of PRDX5 and that it inhibits PRDX5 activity. Here, we show that the PRDX family more broadly is subject to S-acylation at the Cp site of all PRDXs and that PRDX S-acylation dynamically responds to cellular ROS levels. Using activity-based fluorescent imaging with DPP-Red, a red-shifted fluorescent indicator for acyl-protein thioesterase (APT) activity, we also discover that the instigation of ROS-stress via exogenous H2O2 activates both the cytosolic and mitochondrial APTs, whereas epidermal growth factor (EGF)-stimulated endogenous H2O2 deactivates the cytosolic APTs. These results indicate that APTs help tune H2O2 signal transduction and ROS protection through PRDX S-deacylation.

Keywords:  PRDX peroxiredoxin; ROS; S-palmitoylation; fluorescent probe; hydrogen peroxide; protein lipidation

DOI:  https://doi.org/10.1016/j.chembiol.2025.01.009
Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00038-8. [Epub ahead of print]

Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.

Woo Yong Park, Claudia Montufar, Elma Zaganjor.

  Mitochondrial metabolism, signaling, and dynamics are key regulators of cell fate. While glycolysis supports stemness, mitochondrial expansion and oxidative phosphorylation (OXPHOS) facilitate differentiation. This forum presents emerging evidence that the type of substrate, whether amino acids, carbohydrates, or fatty acids, oxidized by mitochondria significantly influences differentiation outcomes.

Keywords:  OXPHOS; amino acids; differentiation; fatty acids; glucose; mitochondria

DOI:  https://doi.org/10.1016/j.tcb.2025.02.004
Nature. 2025 Feb 26.

A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.

Hefei Zhang, Xuhang Li, L Tenzin Tseyang, Gabrielle E Giese, Hui Wang, Bo Yao, Jingyan Zhang, Rachel L Neve, Elizabeth A Shank, Jessica B Spinelli, L Safak Yilmaz, Albertha J M Walhout.

Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring1-6. However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans. Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes7, we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.

DOI: https://doi.org/10.1038/s41586-025-08635-6
Nat Struct Mol Biol. 2025 Feb 26.

Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site.

Shatabdi Roy-Chowdhury, Seil Jang, Fayal Abderemane-Ali, Fiona Naughton, Michael Grabe, Daniel L Minor.

Polyunsaturated fatty acid (PUFA) lipids modulate the neuronal and microglial leak potassium channel K2P13.1 (THIK1) and other voltage-gated ion channel (VGIC) superfamily members through poorly understood mechanisms. Here we present cryo-electron microscopy structures of human THIK1 and mutants, revealing a unique two-chamber aqueous inner cavity obstructed by a hydrophilic barrier important for gating, the flow restrictor, and a P1-M4 intersubunit interface lipid at a site, the PUFA site, corresponding to the K2P small-molecule modulator pocket. This overlap, together with functional studies, indicates that PUFA site lipids are THIK1 cofactors. Comparison with a PUFA-responsive VGIC, Kv7.1, reveals a shared modulatory role for the pore domain intersubunit interface, providing a framework for understanding PUFA action on the VGIC superfamily. Our findings reveal the distinct THIK1 architecture, highlight the importance of the P1-M4 interface for K2P control by natural and synthetic ligands and should aid in the development of THIK subfamily modulators for neuroinflammation and autism.

DOI: https://doi.org/10.1038/s41594-024-01476-3