bims-mimbat 2025-03-23 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2025–03–23
eight papers selected by
José Carlos de Lima-Júnior, Washington University

Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
The choice of diet is determinative for the manifestation of UCP1-dependent diet-induced thermogenesis.
In-cell architecture of the mitochondrial respiratory chain.
ATP synthesis of Enterococcus hirae V-ATPase driven by sodium motive force.
Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel.
A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain.
Absence of intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.
Structures and mechanism of human mitochondrial pyruvate carrier.

J Clin Invest. 2025 Mar 17. pii: e185340. [Epub ahead of print]135(6):

Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.

Yu-Sheng Yeh, Trent D Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J Schopfer, Adam C Straub, Jaehyung Cho, Irfan J Lodhi, Babak Razani.

  Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.

Keywords:  Adipose tissue; Endocrinology; Lysosomes; Metabolism; Obesity; Therapeutics

DOI:  https://doi.org/10.1172/JCI185340
Am J Physiol Endocrinol Metab. 2025 Mar 17.

The choice of diet is determinative for the manifestation of UCP1-dependent diet-induced thermogenesis.

Raman Ahluwalia, Ineke H N Luijten, Celso P B Sousa-Filho, G Ruda F Braz, Natasa Petrovic, Irina G Shabalina, Barbara Cannon, Jan Nedergaard.

  The existence of the phenomenon of diet-induced thermogenesis - and its possible mediation by UCP1 in brown adipose tissue - has long been, and is presently, an important metabolic controversy. Particularly, several recent studies have failed to observe the hallmark of the phenomenon: augmentation of diet-induced obesity in UCP1-ablated mice, thus further casting doubt on the possible importance of this thermogenesis for human metabolic control. However, scrutiny of the experimental details revealed important procedural differences between experiments that did not or did show this augmentation of diet-induced obesity. Particularly, there were notable differences between the commercial diets used (Research-Diets or Ssniff). We therefore tested to what degree these differences would suffice to explain the absence of a UCP1 effect. Wildtype mice fed Research-Diets high-fat diet became obese but UCP1-ablated mice became even more obese, as expected if UCP1-dependent diet-induced thermogenesis exists. Mice fed the Ssniff high-fat diet became less obese than those on the Research-Diets food - and, importantly, no effect of UCP1 ablation was seen. The result with the Research-Diets diet was fully due to differences in total fat mass and not explainable by differences in food intake. The two diets are different in carbohydrate (sucrose) and lipid (lard versus palm oil) composition and in texture and taste. Probably some of these factors explain the difference but the important conclusion is that when an appropriate diet was offered, the body weight manifestation of UCP1-dependent diet-induced thermogenesis was a reproducible phenomenon that may have significance also for human metabolic control.

Keywords:  UCP1; brown adipose tissue; diet-induced obesity; diet-induced thermogenesis; high-fat diet

DOI:  https://doi.org/10.1152/ajpendo.00038.2025
Science. 2025 Mar 21. 387(6740): 1296-1301

In-cell architecture of the mitochondrial respiratory chain.

Florent Waltz, Ricardo D Righetto, Lorenz Lamm, Thalia Salinas-Giegé, Ron Kelley, Xianjun Zhang, Martin Obr, Sagar Khavnekar, Abhay Kotecha, Benjamin D Engel.

Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo-electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo-electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.

DOI: https://doi.org/10.1126/science.ads8738
J Biol Chem. 2025 Mar 19. pii: S0021-9258(25)00271-6. [Epub ahead of print] 108422

ATP synthesis of Enterococcus hirae V-ATPase driven by sodium motive force.

Akihiro Otomo, Lucy Gao Hui Zhu, Yasuko Okuni, Mayuko Yamamoto, Ryota Iino.

  V-ATPases generally function as ion pumps driven by ATP hydrolysis in the cell, but their capability of ATP synthesis remains largely unexplored. Here we show ATP synthesis of Na+-transporting Enterococcus hirae V-ATPase (EhVoV1) driven by electrochemical potential gradient of Na+ across the membrane (sodium motive force, smf). We reconstituted EhVoV1 into liposome and performed a luciferin/luciferase-based assay to analyze ATP synthesis quantitatively. Our result demonstrates that EhVoV1 synthesizes ATP with a rate of 4.7 s-1 under high smf (269.3 mV). The Michaelis constants for ADP (21 μM) and inorganic phosphate (2.1 mM) in ATP synthesis reaction were comparable to those for ATP synthases, suggesting similar substrate affinities among rotary ATPases regardless of their physiological functions. Both components of smf, Na+ concentration gradient across the membrane (ΔpNa) and membrane potential (Δψ), contributed to ATP synthesis, with ΔpNa showing a slightly larger impact. At the equilibrium points where smf and Gibbs free energy of ATP synthesis are balanced, EhVoV1 showed reversible reactions between ATP synthesis and hydrolysis. The obtained Na+/ATP ratio (3.2 ± 0.4) closely matched the value expected from the structural symmetry ratio between EhVo and EhV1 (10/3 = 3.3), indicating tight coupling between ATP synthesis/hydrolysis and Na+ transport. These results reveal inherent functional reversibility of EhVoV1. We propose that physiological function of EhVoV1in vivo is determined by relatively small smf against large Gibbs free energy of ATP synthesis, in addition to the absence of inhibitory mechanisms of ATP hydrolysis which are known for ATP synthases.

Keywords:  ATP; ATP synthase; ATP synthesis; ATPase; V-ATPase; ion pump; liposome; molecular motor; rotary ATPase; sodium transport

DOI:  https://doi.org/10.1016/j.jbc.2025.108422
Cell Death Differ. 2025 Mar 19.

Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel.

Amrendra Kumar, Juliana da Fonseca Rezende E Mello, Yangyu Wu, Daniel Morris, Ikram Mezghani, Erin Smith, Stephane Rombauts, Peter Bossier, Juno Krahn, Fred J Sigworth, Nelli Mnatsakanyan.

Mammalian mitochondria undergo Ca2+-induced and cyclosporinA (CsA)-regulated permeability transition (mPT) by activating the mitochondrial permeability transition pore (mPTP) situated in mitochondrial inner membranes. Ca2+-induced prolonged openings of mPTP under certain pathological conditions result in mitochondrial swelling and rupture of the outer membrane, leading to mitochondrial dysfunction and cell death. While the exact molecular composition and structure of mPTP remain unknown, mammalian ATP synthase was reported to form voltage and Ca2+-activated leak channels involved in mPT. Unlike in mammals, mitochondria of the crustacean Artemia franciscana have the ability to accumulate large amounts of Ca2+ without undergoing the mPT. Here, we performed structural and functional analysis of A. franciscana ATP synthase to study the molecular mechanism of mPTP inhibition in this organism. We found that the channel formed by the A. franciscana ATP synthase dwells predominantly in its inactive state and is insensitive to Ca2+, in contrast to porcine heart ATP synthase. Single-particle cryo-electron microscopy (cryo-EM) analysis revealed distinct structural features in A. franciscana ATP synthase compared with mammals. The stronger density of the e-subunit C-terminal region and its enhanced interaction with the c-ring were found in A. franciscana ATP synthase. These data suggest an inactivation mechanism of the ATP synthase leak channel and its possible contribution to the lack of mPT in this organism.

DOI: https://doi.org/10.1038/s41418-025-01476-w
Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2416162122

A splendid molecular factory: De- and reconstruction of the mammalian respiratory chain.

Lukas Rimle, Ben P Phillips, Isabela M Codo Costa Barra, Noëlle Arnold, Charlie Hennebert, Thomas Meier, Christoph von Ballmoos.

  Mitochondrial respiratory complexes I to IV and the F1Fo-ATP synthase (complex V) are large protein assemblies producing the universal cellular energy currency adenosine triphosphate (ATP). Individual complexes have been extensively studied in vitro, but functional co-reconstitution of several mammalian complexes into proteoliposomes, in particular, the combination of a primary pump with the ATP synthase, is less well understood. Here, we present a generic and scalable strategy to purify mammalian respiratory complexes I, III and the ATP synthase from enriched mitochondria in enzymatically fully active form, and procedures to reassemble the complexes into liposomes. A robust functionality can be shown by in situ monitoring of ATP synthesis rates and by using selected inhibitors of the respiratory chain complexes. By inclusion of cytochrome c oxidase, our procedures allowed us to reconstruct the entire mitochondrial respiratory chain (complexes I, III, IV, and V) in ubiquinone Q10 containing liposomes, demonstrating oxidative phosphorylation by nicotinamide adenine dinucleotide hydrogen driven ATP synthesis. The system was fully coupled at all levels and was used to probe cardiolipin as an essential component to activate the mammalian respiratory chain. Structural characterization using electron cryomicroscopy allowed us to resolve apo-state complex III and complex V at high and medium resolution, respectively, using in silico particle sorting, confirming the presence of all protein subunits and cofactors in native stoichiometry and conformation. The reported findings will facilitate future endeavors to characterize or modulate these key bioenergetic processes.

Keywords:  artificial ATP production; cryo-EM; mitochondria; oxidative phosphorylation; respiratory chain

DOI:  https://doi.org/10.1073/pnas.2416162122
J Clin Invest. 2025 Mar 18. pii: e181754. [Epub ahead of print]

Absence of intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.

Yongbin Chen, Scott M Johnson, Stephanie D Burr, Davide Povero, Aaron M Anderson, Cailin E McMahon, Jun Liu.

  The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet, their coordinated regulation remains undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolishes diet-induced hypertriglyceridemia and significantly attenuates atherogenesis in mice. These effects are attributed to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increases circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalizes plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhances the stability of LPL protein in adipocytes, a phenomenon that can be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reduce circulating TGs.

Keywords:  Adipose tissue; Atherosclerosis; Endocrinology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI181754
Nature. 2025 Mar 18.

Structures and mechanism of human mitochondrial pyruvate carrier.

Jiaming Liang, Junhui Shi, Ailong Song, Meihua Lu, Kairan Zhang, Meng Xu, Gaoxingyu Huang, Peilong Lu, Xudong Wu, Dan Ma.

Mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex essential for uptake of pyruvate into matrix as the primary carbon source for tricarboxylic acid (TCA) cycle1,2. Here, we report six cryo-EM structures of human MPC in three different states: three structures obtained at different conditions in intermembrane space (IMS)-open state with highest resolution of 3.2 Å, a structure of pyruvate-treated MPC in occluded state at 3.7 Å, and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 Å and 3.0 Å, respectively. MPC is assigned into a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2-symmetry. Approximate rigid body movements occur between the IMS-open state and the occluded state, while structural changes primarily on the matrix side facilitate the transition between the occluded state and the matrix-facing state, revealing the alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide important insights into the mechanisms underlying MPC-mediated substrate transport, and the recognition and inhibition by UK5099, which will facilitate future drug development targeting MPC.

DOI: https://doi.org/10.1038/s41586-025-08873-8