bims-mimbat 2024-09-15 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒09‒15
eight papers selected by
José Carlos de Lima-Júnior, Washington University

m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1.
Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.
Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.
Chemiosmotic nutrient transport in synthetic cells powered by electrogenic antiport coupled to decarboxylation.
Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.
IL-1β promotes adipogenesis by directly targeting adipocyte precursors.
Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.

Cell Metab. 2024 Sep 04. pii: S1550-4131(24)00333-4. [Epub ahead of print]

m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1.

Ling Xiao, Dario F De Jesus, Cheng-Wei Ju, Jiang Bo Wei, Jiang Hu, Ava DiStefano-Forti, Tadataka Tsuji, Cheryl Cero, Ville Männistö, Suvi M Manninen, Siying Wei, Oluwaseun Ijaduola, Matthias Blüher, Aaron M Cypess, Jussi Pihlajamäki, Yu-Hua Tseng, Chuan He, Rohit N Kulkarni.

  Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14) modifies the BAT secretome to improve systemic insulin sensitivity independent of UCP1. Using lipidomics, we identify prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as BAT-secreted insulin sensitizers. PGE2 and PGF2a inversely correlate with insulin sensitivity in humans and protect mice from high-fat-diet-induced insulin resistance by suppressing specific AKT phosphatases. Mechanistically, METTL14-mediated m6A promotes the decay of PTGES2 and CBR1, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of Ptges2 or Cbr1 reverses the insulin-sensitizing effects in M14KO mice. Overall, these findings reveal a novel biological mechanism through which m6A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity.

Keywords:  METTL14; brown fat; human; insulin sensitivity; inter-organ communication; m(6)A; prostaglandins

DOI:  https://doi.org/10.1016/j.cmet.2024.08.006
FEBS Lett. 2024 Sep 11.

Quinone chemistry in respiratory complex I involves protonation of a conserved aspartic acid residue.

Caroline Harter, Frédéric Melin, Franziska Hoeser, Petra Hellwig, Daniel Wohlwend, Thorsten Friedrich.

  Respiratory complex I is a central metabolic enzyme coupling NADH oxidation and quinone reduction with proton translocation. Despite the knowledge of the structure of the complex, the coupling of both processes is not entirely understood. Here, we use a combination of site-directed mutagenesis, biochemical assays, and redox-induced FTIR spectroscopy to demonstrate that the quinone chemistry includes the protonation and deprotonation of a specific, conserved aspartic acid residue in the quinone binding site (D325 on subunit NuoCD in Escherichia coli). Our experimental data support a proposal derived from theoretical considerations that deprotonation of this residue is involved in triggering proton translocation in respiratory complex I.

Keywords:  Escherichia coli; NADH dehydrogenase; NADH:quinone oxidoreductase; iron–sulfur cluster; proton‐coupled electron transfer; quinone reduction; redox‐induced FTIR spectroscopy; site‐directed mutagenesis

DOI:  https://doi.org/10.1002/1873-3468.15013
EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.

  The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI:  https://doi.org/10.1038/s44318-024-00219-w
Proc Natl Acad Sci U S A. 2024 Sep 17. 121(38): e2407479121

Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.

Yu Liu, Chenghan Li, J Alfredo Freites, Douglas J Tobias, Gregory A Voth.

  Human voltage-gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single-proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild-type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two-proton knock-on model is proposed to mathematically explain the electrophysiological measurements of the pH-dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage.

Keywords:  ion selectivity; molecular dynamics; proton channel; proton transport

DOI:  https://doi.org/10.1073/pnas.2407479121
Nat Commun. 2024 Sep 12. 15(1): 7976

Chemiosmotic nutrient transport in synthetic cells powered by electrogenic antiport coupled to decarboxylation.

Miyer F Patiño-Ruiz, Zaid Ramdhan Anshari, Bauke Gaastra, Dirk J Slotboom, Bert Poolman.

Cellular homeostasis depends on the supply of metabolic energy in the form of ATP and electrochemical ion gradients. The construction of synthetic cells requires a constant supply of energy to drive membrane transport and metabolism. Here, we provide synthetic cells with long-lasting metabolic energy in the form of an electrochemical proton gradient. Leveraging the L-malate decarboxylation pathway we generate a stable proton gradient and electrical potential in lipid vesicles by electrogenic L-malate/L-lactate exchange coupled to L-malate decarboxylation. By co-reconstitution with the transporters GltP and LacY, the synthetic cells maintain accumulation of L-glutamate and lactose over periods of hours, mimicking nutrient feeding in living cells. We couple the accumulation of lactose to a metabolic network for the generation of intermediates of the glycolytic and pentose phosphate pathways. This study underscores the potential of harnessing a proton motive force via a simple metabolic network, paving the way for the development of more complex synthetic systems.

DOI: https://doi.org/10.1038/s41467-024-52085-z
J Lipid Res. 2024 Sep 06. pii: S0022-2275(24)00146-9. [Epub ahead of print] 100641

Disruption of nucleotide biosynthesis reprograms mitochondrial metabolism to inhibit adipogenesis.

Julia A Pinette, Jacob W Myers, Woo Yong Park, Heather G Bryant, Alex M Eddie, Genesis A Wilson, Claudia Montufar, Zayedali Shaikh, Zer Vue, Elizabeth R Nunn, Ryoichi Bessho, Matthew A Cottam, Volker H Haase, Antentor O Hinton, Jessica B Spinelli, Jean-Philippe Cartailler, Elma Zaganjor.

  A key organismal response to overnutrition involves the development of new adipocytes through the process of adipogenesis. Preadipocytes sense changes in the systemic nutrient status and metabolites can directly modulate adipogenesis. We previously identified a role of de novo nucleotide biosynthesis in adipogenesis induction, whereby inhibition of nucleotide biosynthesis suppresses the expression of the transcriptional regulators PPARγ and C/EBPα. Here, we set out to identify the global transcriptomic changes associated with the inhibition of nucleotide biosynthesis. Through RNA sequencing (RNAseq), we discovered that mitochondrial signatures were the most altered in response to inhibition of nucleotide biosynthesis. Blocking nucleotide biosynthesis induced rounded mitochondrial morphology, and altered mitochondrial function, and metabolism, reducing levels of tricarboxylic acid cycle intermediates, and increasing fatty acid oxidation (FAO). The loss of mitochondrial function induced by suppression of nucleotide biosynthesis was rescued by exogenous expression of PPARγ. Moreover, inhibition of FAO restored PPARγ expression, mitochondrial protein expression, and adipogenesis in the presence of nucleotide biosynthesis inhibition, suggesting a regulatory role of nutrient oxidation in differentiation. Collectively, our studies shed light on the link between substrate oxidation and transcription in cell fate determination.

Keywords:  adipocytes; adipogenesis; fatty acid oxidation; lipid droplets; metabolism; nucleotides; purine; pyrimidine

DOI:  https://doi.org/10.1016/j.jlr.2024.100641
Nat Commun. 2024 Sep 11. 15(1): 7957

IL-1β promotes adipogenesis by directly targeting adipocyte precursors.

Kaisa Hofwimmer, Joyce de Paula Souza, Narmadha Subramanian, Milica Vujičić, Leila Rachid, Hélène Méreau, Cheng Zhao, Erez Dror, Emelie Barreby, Niklas K Björkström, Ingrid Wernstedt Asterholm, Marianne Böni-Schnetzler, Daniel T Meier, Marc Y Donath, Jurga Laurencikiene.

Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.

DOI: https://doi.org/10.1038/s41467-024-51938-x
Nat Metab. 2024 Sep 11.

Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.

Haoming Wang, John W Vant, Andrew Zhang, Richard G Sanchez, Youjun Wu, Mary L Micou, Vincent Luczak, Zachary Whiddon, Natasha M Carlson, Seungyoon B Yu, Mirna Jabbo, Seokjun Yoon, Ahmed A Abushawish, Majid Ghassemian, Takeya Masubuchi, Quan Gan, Shigeki Watanabe, Eric R Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.

Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.

DOI: https://doi.org/10.1038/s42255-024-01121-9