bims-mimbat 2025-02-23 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2025–02–23
eight papers selected by
José Carlos de Lima-Júnior, Washington University

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.
TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
Replacement of phenyl substituents at phosphorus by hexyl ones in 2-(2-hydroxyaryl)vinylphosphonium salts can tune the nature of the induced proton transport through lipid membranes.
Structural dynamics of human fatty acid synthase in the condensing cycle.
Cooperative nutrient scavenging is an evolutionary advantage in cancer.

Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.

Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.

  Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Cell Metab. 2025 Feb 14. pii: S1550-4131(25)00012-9. [Epub ahead of print]

adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.

Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L Ståhl, Yvonne Böttcher, Maria Keller, Peter Kovacs, Alastair G Kerr, Dominique Langin, Christian Wolfrum, Matthias Blüher, Natalie Krahmer, Lucas Massier, Niklas Mejhert, Mikael Rydén.

We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.

DOI: https://doi.org/10.1016/j.cmet.2025.01.012
Sci Adv. 2025 Feb 21. 11(8): eadr3723

TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.

Pradeep K Sheokand, Andrew M James, Benjamin Jenkins, Pawel K Lysyganicz, Denis Lacabanne, Martin S King, Edmund R S Kunji, Symeon Siniossoglou, Albert Koulman, Michael P Murphy, Kasparas Petkevicius.

The diversity of cellular phospholipids, crucial for membrane homeostasis and function, arises from enzymatic remodeling of their fatty acyl chains. In this work, we reveal that poorly understood TRAM-LAG1-CLN8 domain (TLCD)-containing proteins are phospholipid remodeling enzymes. We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates previously undescribed fatty acid and thiamine (vitamin B1) esters as its secondary products. Furthermore, we establish that human TLCD protein CLN8, mutations of which cause fatal neurodegenerative Batten disease, is a lysophosphatidylglycerol acyltransferase. We show that CLN8 catalyzes the essential step in the biosynthesis of bis(monoacylglycero)phosphate, a phospholipid critical for lysosome function. Our study unveils a family of acyltransferases integral to cellular membrane phospholipid homeostasis and human disease.

DOI: https://doi.org/10.1126/sciadv.adr3723
Nature. 2025 Feb 19.

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.

Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.

DOI: https://doi.org/10.1038/s41586-025-08590-2
Biochim Biophys Acta Biomembr. 2025 Feb 19. pii: S0005-2736(25)00011-2. [Epub ahead of print] 184417

Replacement of phenyl substituents at phosphorus by hexyl ones in 2-(2-hydroxyaryl)vinylphosphonium salts can tune the nature of the induced proton transport through lipid membranes.

Tatyana I Rokitskaya, Ljudmila S Khailova, Anna G Strelnik, Elena A Kotova, Vladimir F Mironov, Dmitry A Tatarinov, Yuri N Antonenko.

  2-(2-hydroxyaryl)vinylphosphonium salts are zwitterionic protonophores previously shown to induce proton transport across lipid membranes via cyclic deprotonation and protonation of the hydroxyl group. Here, we examine the impact of the kind of substituents at phosphorus on the protonophoric activity of these compounds. In particular, replacement of all the three phenyl groups at the phosphorus atom of the 2-(2-hydroxyaryl)vinyl(triphenyl)phosphonium salt (2HVPPh3) by hexyl chains (2HVPHex3) led to a tremendous increase in electric current induced by the phosphonium salt across planar bilayer lipid membranes (BLM). Remarkably, the BLM conductance quadratically increased with increasing 2HVPHex3 concentration, whereas a linear concentration dependence of the BLM current was observed for 2HVPPh3, 2HVPHexPh2 ((hexyl)diphenyl) and 2HVPHex2Ph ((dihexyl)phenyl), i.e., in the presence of at least one phenyl substituent at the phosphorus atom. Proton selectivity of the 2HVPHex3-induced electric current was close to perfect in membranes formed of diphytanylphosphatidylcholine with the decreased dipole potential, but rather low in membranes formed of the usual synthetic lipid - diphytanoylphosphatidylcholine. We hypothesize that the proton transport across BLM is carried out by 2HVPHex3 dimers. By contrast, the uncoupling activity of 2HVPHex3 in isolated rat liver mitochondria was observed at similar concentrations, as found for the compounds with phenyl substituents, thereby indicating that dimers do not play a key role in the uncoupling process. At the same time, the rate of 2HVPHex3-induced mitochondrial swelling under the deenergized conditions in potassium acetate medium, reflecting the protonophoric activity of the compound in mitochondria, significantly exceeded that for other compounds.

Keywords:  Lipid membrane; Mitochondrial uncoupling; Phosphonium salts; Proton transport

DOI:  https://doi.org/10.1016/j.bbamem.2025.184417
Nature. 2025 Feb 20.

Structural dynamics of human fatty acid synthase in the condensing cycle.

Wooyoung Choi, Chengmin Li, Yifei Chen, Yongqiang Wang, Yifan Cheng.

Long chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyze all chemical reactions needed for de novo fatty acid synthesis1. While the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyzes such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293 for single particle cryogenic electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured the conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyze particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, we reveal that FASN function does not require large rotational motion between its two major functional domains during the condensing cycle, and that the catalytic reactions in condensing cycle carried out by two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle.

DOI: https://doi.org/10.1038/s41586-025-08782-w
Nature. 2025 Feb 19.

Cooperative nutrient scavenging is an evolutionary advantage in cancer.

Gizem Guzelsoy, Setiembre D Elorza, Manon Ros, Logan T Schachtner, Makiko Hayashi, Spencer Hobson-Gutierrez, Parker Rundstrom, Julia S Brunner, Ray Pillai, William E Walkowicz, Lydia W S Finley, Maxime Deforet, Thales Papagiannakopoulos, Carlos Carmona-Fontaine.

The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.

DOI: https://doi.org/10.1038/s41586-025-08588-w