bims-mimbat 2024-06-02 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒06‒02
seven papers selected by
José Carlos de Lima-Júnior, Washington University

High-resolution in situ structures of mammalian respiratory supercomplexes.
Rab30 facilitates lipid homeostasis during fasting.
Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.
UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.
Conformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate.
Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
Proton-coupled transport mechanism of the efflux pump NorA.

Nature. 2024 May 29.

High-resolution in situ structures of mammalian respiratory supercomplexes.

Wan Zheng, Pengxin Chai, Jiapeng Zhu, Kai Zhang.

Mitochondria play a pivotal part in ATP energy production through oxidative phosphorylation, which occurs within the inner membrane through a series of respiratory complexes1-4. Despite extensive in vitro structural studies, determining the atomic details of their molecular mechanisms in physiological states remains a major challenge, primarily because of loss of the native environment during purification. Here we directly image porcine mitochondria using an in situ cryo-electron microscopy approach. This enables us to determine the structures of various high-order assemblies of respiratory supercomplexes in their native states. We identify four main supercomplex organizations: I1III2IV1, I1III2IV2, I2III2IV2 and I2III4IV2, which potentially expand into higher-order arrays on the inner membranes. These diverse supercomplexes are largely formed by 'protein-lipids-protein' interactions, which in turn have a substantial impact on the local geometry of the surrounding membranes. Our in situ structures also capture numerous reactive intermediates within these respiratory supercomplexes, shedding light on the dynamic processes of the ubiquinone/ubiquinol exchange mechanism in complex I and the Q-cycle in complex III. Structural comparison of supercomplexes from mitochondria treated under different conditions indicates a possible correlation between conformational states of complexes I and III, probably in response to environmental changes. By preserving the native membrane environment, our approach enables structural studies of mitochondrial respiratory supercomplexes in reaction at high resolution across multiple scales, from atomic-level details to the broader subcellular context.

DOI: https://doi.org/10.1038/s41586-024-07488-9
Nat Commun. 2024 May 25. 15(1): 4469

Rab30 facilitates lipid homeostasis during fasting.

Danielle M Smith, Brian Y Liu, Michael J Wolfgang.

To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.

DOI: https://doi.org/10.1038/s41467-024-48959-x
Nat Metab. 2024 May;6(5): 847-860

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Sungwoo Choi, Ju-Gyeong Kang, Yen T H Tran, Sun-Hye Jeong, Kun-Young Park, Hyemi Shin, Young Hoon Kim, Myungsun Park, Hahn Nahmgoong, Taejun Seol, Haeyon Jeon, Yeongmin Kim, Sanghee Park, Hee-Joo Kim, Min-Seob Kim, Xiaoxu Li, Maroun Bou Sleiman, Eries Lee, Jinhyuk Choi, David Eisenbarth, Sang Heon Lee, Suhyeon Cho, David D Moore, Johan Auwerx, Il-Young Kim, Jae Bum Kim, Jong-Eun Park, Dae-Sik Lim, Jae Myoung Suh.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

DOI: https://doi.org/10.1038/s42255-024-01045-4
FASEB J. 2024 Jun 15. 38(11): e23709

UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Azariyas A Challa, Pablo Vidal, Santosh K Maurya, Chandan K Maurya, Lisa A Baer, Yang Wang, Natasha Maria James, Parth J Pardeshi, Matthew Fasano, Andrew N Carley, Kristin I Stanford, E Douglas Lewandowski.

  Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of β-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-β1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Keywords:  UCP1; brown adipose tissue; cardiac metabolic remodeling; pathological hypertrophy; pressure overload

DOI:  https://doi.org/10.1096/fj.202400922R
Nat Commun. 2024 May 31. 15(1): 4655

Conformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate.

Jingyu Zhan, Allison Zeher, Rick Huang, Wai Kwan Tang, Lisa M Jenkins, Di Xia.

The human AAA-ATPase Bcs1L translocates the fully assembled Rieske iron-sulfur protein (ISP) precursor across the mitochondrial inner membrane, enabling respiratory Complex III assembly. Exactly how the folded substrate is bound to and released from Bcs1L has been unclear, and there has been ongoing debate as to whether subunits of Bcs1L act in sequence or in unison hydrolyzing ATP when moving the protein cargo. Here, we captured Bcs1L conformations by cryo-EM during active ATP hydrolysis in the presence or absence of ISP substrate. In contrast to the threading mechanism widely employed by AAA proteins in substrate translocation, subunits of Bcs1L alternate uniformly between ATP and ADP conformations without detectable intermediates that have different, co-existing nucleotide states, indicating that the subunits act in concert. We further show that the ISP can be trapped by Bcs1 when its subunits are all in the ADP-bound state, which we propose to be released in the apo form.

DOI: https://doi.org/10.1038/s41467-024-49029-y
Nat Commun. 2024 May 30. 15(1): 4605

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.

Shuai Yan, Anna Santoro, Micah J Niphakis, Antonio M Pinto, Christopher L Jacobs, Rasheed Ahmad, Radu M Suciu, Bryan R Fonslow, Rachel A Herbst-Graham, Nhi Ngo, Cassandra L Henry, Dylan M Herbst, Alan Saghatelian, Barbara B Kahn, Evan D Rosen.

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

DOI: https://doi.org/10.1038/s41467-024-48220-5
Nat Commun. 2024 May 27. 15(1): 4494

Proton-coupled transport mechanism of the efflux pump NorA.

Jianping Li, Yan Li, Akiko Koide, Huihui Kuang, Victor J Torres, Shohei Koide, Da-Neng Wang, Nathaniel J Traaseth.

Efflux pump antiporters confer drug resistance to bacteria by coupling proton import with the expulsion of antibiotics from the cytoplasm. Despite efforts there remains a lack of understanding as to how acid/base chemistry drives drug efflux. Here, we uncover the proton-coupling mechanism of the Staphylococcus aureus efflux pump NorA by elucidating structures in various protonation states of two essential acidic residues using cryo-EM. Protonation of Glu222 and Asp307 within the C-terminal domain stabilized the inward-occluded conformation by forming hydrogen bonds between the acidic residues and a single helix within the N-terminal domain responsible for occluding the substrate binding pocket. Remarkably, deprotonation of both Glu222 and Asp307 is needed to release interdomain tethering interactions, leading to opening of the pocket for antibiotic entry. Hence, the two acidic residues serve as a "belt and suspenders" protection mechanism to prevent simultaneous binding of protons and drug that enforce NorA coupling stoichiometry and confer antibiotic resistance.

DOI: https://doi.org/10.1038/s41467-024-48759-3