bims-mimbat 2023-02-05 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023‒02‒05
sixteen papers selected by
José Carlos de Lima-Júnior
Washington University

Regulation of beige adipocyte thermogenesis by the cold-repressed ER protein NNAT.
RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1α.
Membrane-domain mutations in respiratory complex I impede catalysis but do not uncouple proton pumping from ubiquinone reduction.
Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice.
TRPM8 thermosensation in poikilotherms mediates both skin colour and locomotor performance responses to cold temperature.
DNA-PKcs and ATM modulate mitochondrial ADP-ATP exchange as an oxidative stress checkpoint mechanism.
Mitochondrial B-oxidation of adipose-derived fatty acids by osteoblast fuels parathyroid hormone-induced bone formation.
A loosely coordinated interaction site for arachidonic acid on ASICs.
The evolution of the human mitochondrial bc1 complex- adaptation for reduced rate of superoxide production?
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.
IP3 receptor trafficking at the ER-mitochondria contacts impacts on mitochondrial Ca2+ homeostasis and metabolism.
Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.
Slow TCA flux and ATP production in primary solid tumours but not metastases.
A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.
Anaplerosis in action.
Mechanistic insights into robust cardiac I Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues.

Mol Metab. 2023 Jan 25. pii: S2212-8778(23)00013-3. [Epub ahead of print] 101679

Regulation of beige adipocyte thermogenesis by the cold-repressed ER protein NNAT.

Kyung-Mi Choi, Christopher Y Ko, Sung-Min An, Seung-Hee Cho, Douglas J Rowland, Jung Hak Kim, Anna Fasoli, Abhijit J Chaudhari, Donald M Bers, John C Yoon.

  OBJECTIVE: Cold stimuli trigger the conversion of white adipose tissue into beige adipose tissue, which is capable of non-shivering thermogenesis. However, what process drives this activation of thermogenesis in beige fat is not well understood. Here, we examine the ER protein NNAT as a regulator of thermogenesis in adipose tissue.METHODS: We investigated the regulation of adipose tissue NNAT expression in response to changes in ambient temperature. We also evaluated the functional role of NNAT in thermogenic regulation using Nnat null mice and primary adipocytes that lack or overexpress NNAT.
RESULTS: Cold exposure or treatment with a β3-adrenergic agonist reduces the expression of adipose tissue NNAT in mice. Genetic disruption of Nnat in mice enhances inguinal adipose tissue thermogenesis. Nnat null mice exhibit improved cold tolerance both in the presence and absence of UCP1. Gain-of-function studies indicate that ectopic expression of Nnat abolishes adrenergic receptor-mediated respiration in beige adipocytes. NNAT physically interacts with the ER Ca2+-ATPase (SERCA) in adipocytes and inhibits its activity, impairing Ca2+ transport and heat dissipation. We further demonstrate that NHLRC1, an E3 ubiquitin protein ligase implicated in proteasomal degradation of NNAT, is induced by cold exposure or β3-adrenergic stimulation, thus providing regulatory control at the protein level. This serves to link cold stimuli to NNAT degradation in adipose tissue, which in turn leads to enhanced SERCA activity.
CONCLUSIONS: Our study implicates NNAT in the regulation of adipocyte thermogenesis.

Keywords:  Beige fat; NHLRC1; NNAT; SERCA2; Thermogenesis

DOI:  https://doi.org/10.1016/j.molmet.2023.101679
bioRxiv. 2023 Jan 07. pii: 2023.01.06.522985. [Epub ahead of print]

RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1α.

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

Adipose thermogenesis involves specialized mitochondrial function that counteracts metabolic disease through dissipation of chemical energy as heat. However, inflammation present in obese adipose tissue can impair oxidative metabolism. Here, we show that PGC1α, a key governor of mitochondrial biogenesis and thermogenesis, is negatively regulated at the level of mRNA translation by the little-known RNA-binding protein RBM43. Rbm43 is expressed selectively in white adipose depots that have low thermogenic potential, and is induced by inflammatory cytokines. RBM43 suppresses mitochondrial and thermogenic gene expression in a PGC1α-dependent manner and its loss protects cells from cytokine-induced mitochondrial impairment. In mice, adipocyte-selective Rbm43 disruption increases PGC1α translation, resulting in mitochondrial biogenesis and adipose thermogenesis. These changes are accompanied by improvements in glucose homeostasis during diet-induced obesity that are independent of body weight. The action of RBM43 suggests a translational mechanism by which inflammatory signals associated with metabolic disease dampen mitochondrial function and thermogenesis.

DOI: https://doi.org/10.1101/2023.01.06.522985
PNAS Nexus. 2022 Nov;1(5): pgac276

Membrane-domain mutations in respiratory complex I impede catalysis but do not uncouple proton pumping from ubiquinone reduction.

Owen D Jarman, Judy Hirst.

  Respiratory complex I [NADH:ubiquinone (UQ) oxidoreductase] captures the free energy released from NADH oxidation and UQ reduction to pump four protons across an energy-transducing membrane and power ATP synthesis. Mechanisms for long-range energy coupling in complex I have been proposed from structural data but not yet evaluated by robust biophysical and biochemical analyses. Here, we use the powerful bacterial model system Paracoccus denitrificans to investigate 14 mutations of key residues in the membrane-domain Nqo13/ND4 subunit, defining the rates and reversibility of catalysis and the number of protons pumped per NADH oxidized. We reveal new insights into the roles of highly conserved charged residues in lateral energy transduction, confirm the purely structural role of the Nqo12/ND5 transverse helix, and evaluate a proposed hydrated channel for proton uptake. Importantly, even when catalysis is compromised the enzyme remains strictly coupled (four protons are pumped per NADH oxidized), providing no evidence for escape cycles that circumvent blocked proton-pumping steps.

Keywords:  NADH:ubiquinone oxidoreductase; biological energy transduction; electron transport chain; proton pumping; respiratory chain

DOI:  https://doi.org/10.1093/pnasnexus/pgac276
Int J Obes (Lond). 2023 Feb 02.

Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice.

Cong Liu, Zikuan Song, Zhuang Li, Mariëtte R Boon, Milena Schönke, Patrick C N Rensen, Yanan Wang.

OBJECTIVES: Studies in mice have recently linked increased dietary choline consumption to increased incidence of obesity-related metabolic diseases, while several clinical trials have reported an anti-obesity effect of high dietary choline intake. Since the underlying mechanisms by which choline affects obesity are incompletely understood, the aim of the present study was to investigate the role of dietary choline supplementation in adiposity.METHODS: Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism and cardiometabolic diseases, were fed a Western-type diet supplemented with or without choline (1.2%, w/w) for up to 16 weeks.
RESULTS: Dietary choline reduced body fat mass gain, prevented adipocyte enlargement, and attenuated adipose tissue inflammation. Besides, choline ameliorated liver steatosis and damage, associated with an upregulation of hepatic genes involved in fatty acid oxidation. Moreover, choline reduced plasma cholesterol, as explained by a reduction of plasma non-HDL cholesterol. Mechanistically, choline reduced hepatic VLDL-cholesterol secretion and enhanced the selective uptake of fatty acids from triglyceride-rich lipoprotein (TRL)-like particles by brown adipose tissue (BAT), consequently accelerating the clearance of the cholesterol-enriched TRL remnants by the liver.
CONCLUSIONS: In APOE*3-Leiden.CETP mice, dietary choline reduces body fat by enhancing TRL-derived fatty acids by BAT, resulting in accelerated TRL turnover to improve hypercholesterolemia. These data provide a mechanistic basis for the observation in human intervention trials that high choline intake is linked with reduced body weight.

DOI: https://doi.org/10.1038/s41366-023-01269-6
Commun Biol. 2023 Jan 31. 6(1): 127

TRPM8 thermosensation in poikilotherms mediates both skin colour and locomotor performance responses to cold temperature.

Hannan R Malik, Gabriel E Bertolesi, Sarah McFarlane.

Thermoregulation is a homeostatic process to maintain an organism's internal temperature within a physiological range compatible with life. In poikilotherms, body temperature fluctuates with that of the environment, with both physiological and behavioral responses employed to modify body temperature. Changing skin colour/reflectance and locomotor activity are both well-recognized temperature regulatory mechanisms, but little is known of the participating thermosensor/s. We find that Xenopus laevis tadpoles put in the cold exhibit a temperature-dependent, systemic, and rapid melanosome aggregation in melanophores, which lightens the skin. Cooling also induces a reduction in the locomotor performance. To identify the cold-sensor, we focus on transient receptor potential (trp) channel genes from a Trpm family. mRNAs for several Trpms are present in Xenopus tails, and Trpm8 protein is present in skin melanophores. Temperature-induced melanosome aggregation is mimicked by the Trpm8 agonist menthol (WS12) and blocked by a Trpm8 antagonist. The degree of skin lightening induced by cooling is correlated with locomotor performance, and both responses are rapidly regulated in a dose-dependent and correlated manner by the WS12 Trpm8 agonist. We propose that TRPM8 serves as a cool thermosensor in poikilotherms that helps coordinate skin lightening and behavioural locomotor performance as adaptive thermoregulatory responses to cold.

DOI: https://doi.org/10.1038/s42003-023-04489-8
EMBO J. 2023 Feb 02. e112094

DNA-PKcs and ATM modulate mitochondrial ADP-ATP exchange as an oxidative stress checkpoint mechanism.

Wei-Min Chen, Jui-Chung Chiang, Zengfu Shang, Guillermo Palchik, Ciara Newman, Yuanyuan Zhang, Anthony J Davis, Hsinyu Lee, Benjamin Pc Chen.

  DNA-PKcs is a key regulator of DNA double-strand break repair. Apart from its canonical role in the DNA damage response, DNA-PKcs is involved in the cellular response to oxidative stress (OS), but its exact role remains unclear. Here, we report that DNA-PKcs-deficient human cells display depolarized mitochondria membrane potential (MMP) and reoriented metabolism, supporting a role for DNA-PKcs in oxidative phosphorylation (OXPHOS). DNA-PKcs directly interacts with mitochondria proteins ANT2 and VDAC2, and formation of the DNA-PKcs/ANT2/VDAC2 (DAV) complex supports optimal exchange of ADP and ATP across mitochondrial membranes to energize the cell via OXPHOS and to maintain MMP. Moreover, we demonstrate that the DAV complex temporarily dissociates in response to oxidative stress to attenuate ADP-ATP exchange, a rate-limiting step for OXPHOS. Finally, we found that dissociation of the DAV complex is mediated by phosphorylation of DNA-PKcs at its Thr2609 cluster by ATM kinase. Based on these findings, we propose that the coordination between the DAV complex and ATM serves as a novel oxidative stress checkpoint to decrease ROS production from mitochondrial OXPHOS and to hasten cellular recovery from OS.

Keywords:  ANT2; ATM; DNA-PKcs; VDAC2; mitochondrial oxidative stress checkpoint

DOI:  https://doi.org/10.15252/embj.2022112094
JCI Insight. 2023 Feb 02. pii: e165604. [Epub ahead of print]

Mitochondrial B-oxidation of adipose-derived fatty acids by osteoblast fuels parathyroid hormone-induced bone formation.

Nathalie Alekos, Priyanka Kushwaha, Soohyun Kim, Zhu Li, Abdullah Abood, Naomi Dirckx, Susan Aja, Joe Kodama, Jean Garcia-Diaz, Satoru Otsuru, Elizabeth Rendina-Ruedy, Michael J Wolfgang, Ryan C Riddle.

  The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues, like adipose, that can supply energy-dense macronutrients. In the case of intermittent parathyroid hormone treatment (PTH), a strategy used to reduce fracture risk, bone formation is proceeded by a change in systemic lipid homeostasis. To investigate the requirement for fatty acid oxidation by osteoblasts during PTH-induced bone formation, we subjected mice with osteoblast-specific deficiency of mitochondrial long-chain β-oxidation as well as mice with adipocyte-specific deficiency for the PTH receptor or adipose triglyceride lipase to an anabolic treatment regime. PTH increased the release of fatty acids from adipocytes and B-oxidation by osteoblasts, while the genetic mouse models were resistant to the hormone's anabolic effect. Collectively, these data suggest that PTH's anabolic actions requires coordinated signaling between bone and adipose, wherein a lipolytic response liberates fatty acids that are oxidized by osteoblasts to fuel bone formation.

Keywords:  Adipose tissue; Bone Biology; Fatty acid oxidation; Osteoporosis

DOI:  https://doi.org/10.1172/jci.insight.165604
J Gen Physiol. 2023 Mar 06. pii: e202213307. [Epub ahead of print]155(3):

A loosely coordinated interaction site for arachidonic acid on ASICs.

Robert C Klipp, John R Bankston.

DOI: https://doi.org/10.1085/jgp.202213307
J Bioenerg Biomembr. 2023 Feb 04.

The evolution of the human mitochondrial bc1 complex- adaptation for reduced rate of superoxide production?

Hagai Rottenberg.

  The mitochondrial bc1 complex is a major source of mitochondrial superoxide. While bc1-generated superoxide plays a beneficial signaling role, excess production of superoxide lead to aging and degenerative diseases. The catalytic core of bc1 comprises three peptides -cytochrome b, Fe-S protein, and cytochrome c1. All three core peptides exhibit accelerated evolution in anthropoid primates. It has been suggested that the evolution of cytochrome b in anthropoids was driven by a pressure to reduce the production of superoxide. In humans, the bc1 core peptides exhibit anthropoid-specific substitutions that are clustered near functionally critical sites that may affect the production of superoxide. Here we compare the high-resolution structures of bovine, mouse, sheep and human bc1 to identify structural changes that are associated with human-specific substitutions. Several cytochrome b substitutions in humans alter its interactions with other subunits. Most significantly, there is a cluster of seven substitutions, in cytochrome b, the Fe-S protein, and cytochrome c1 that affect the interactions between these proteins at the tether arm of the Fe-S protein and may alter the rate of ubiquinone oxidation and the rate of superoxide production. Another cluster of substitutions near heme bH and the ubiquinone reduction site, Qi, may affect the rate of ubiquinone reduction and thus alter the rate of superoxide production. These results are compatible with the hypothesis that cytochrome b in humans (and other anthropoid primates) evolve to reduce the rate of production of superoxide thus enabling the exceptional longevity and exceptional cognitive ability of humans.

Keywords:  Cytochrome b; Human; Mitochondria; Proton pumping; Superoxide; bc1 complex

DOI:  https://doi.org/10.1007/s10863-023-09957-8
bioRxiv. 2023 Jan 19. pii: 2023.01.19.524708. [Epub ahead of print]

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

Rosario Avolio, Ilenia Agliarulo, Daniela Criscuolo, Daniela Sarnataro, Margherita Auriemma, Sara Pennacchio, Giovanni Calice, Martin Y Ng, Carlotta Giorgi, Paolo Pinton, Barry Cooperman, Matteo Landriscina, Franca Esposito, Danilo Swann Matassa.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

DOI: https://doi.org/10.1101/2023.01.19.524708
Cell Calcium. 2023 Jan 25. pii: S0143-4160(23)00012-X. [Epub ahead of print]110 102700

IP3 receptor trafficking at the ER-mitochondria contacts impacts on mitochondrial Ca2+ homeostasis and metabolism.

Karim Rahhali, Fabio Di Lisa, Nina Kaludercic.

  The close contacts between endoplasmic reticulum and mitochondria (ERMCs) play a key role in metabolic regulation, Ca2+ homeostasis, reactive oxygen species production, and many other cell functions. Nevertheless, it is not fully clear how these contacts dynamically rearrange to support cell functions. In a recent Nature Communications article [1], Katona et al. elegantly showed that motile IP3Rs can be captured at ERMCs to promptly mediate Ca2+ transfer and stimulate mitochondrial oxidative metabolism.

Keywords:  Contact sites; Endoplasmic reticulum; IP(3) receptor; Mitochondria

DOI:  https://doi.org/10.1016/j.ceca.2023.102700
Eur Heart J. 2023 Feb 03. pii: ehad028. [Epub ahead of print]

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

Edgar E Nollet, Inez Duursma, Anastasiya Rozenbaum, Moritz Eggelbusch, Rob C I Wüst, Stephan A C Schoonvelde, Michelle Michels, Mark Jansen, Nicole N van der Wel, Kenneth C Bedi, Kenneth B Margulies, Jeff Nirschl, Diederik W D Kuster, Jolanda van der Velden.

  AIMS: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.METHODS AND RESULTS: Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.
CONCLUSION: Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.

Keywords:  Cardiomyocyte architecture; Hypertrophic cardiomyopathy; Metabolism; Mitochondrial dysfunction; Mitochondrial therapy

DOI:  https://doi.org/10.1093/eurheartj/ehad028
Nature. 2023 Feb 01.

Slow TCA flux and ATP production in primary solid tumours but not metastases.

Caroline R Bartman, Daniel R Weilandt, Yihui Shen, Won Dong Lee, Yujiao Han, Tara TeSlaa, Connor S R Jankowski, Laith Samarah, Noel R Park, Victoria da Silva-Diz, Maya Aleksandrova, Yetis Gultekin, Argit Marishta, Lin Wang, Lifeng Yang, Asael Roichman, Vrushank Bhatt, Taijin Lan, Zhixian Hu, Xi Xing, Wenyun Lu, Shawn Davidson, Martin Wühr, Matthew G Vander Heiden, Daniel Herranz, Jessie Yanxiang Guo, Yibin Kang, Joshua D Rabinowitz.

Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue's major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

DOI: https://doi.org/10.1038/s41586-022-05661-6
Elife. 2023 Feb 01. pii: e82283. [Epub ahead of print]12

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.

Jake P Mann, Xiaowen Duan, Satish Patel, Luis Carlos Tábara, Fabio Scurria, Anna Alvarez-Guaita, Afreen Haider, Ineke Luijten, Matthew Page, Margherita Protasoni, Koini Lim, Sam Virtue, Stephen O'Rahilly, Martin Armstrong, Julien Prudent, Robert K Semple, David B Savage.

  Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.82283
Nat Metab. 2023 Jan;5(1): 5-7

Anaplerosis in action.

PamelaSara E Head, Charles P Venditti.

DOI: https://doi.org/10.1038/s42255-022-00724-4
bioRxiv. 2023 Jan 15. pii: 2023.01.12.523777. [Epub ahead of print]

Mechanistic insights into robust cardiac I Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues.

Briana M Bohannon, Jessica J Jowais, Leif Nyberg, Sara I Liin, H Peter Larsson.

Voltage-gated potassium (K V ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K V channel activators with potential applications in the treatment of arrhythmogenic disorders such as Long QT Syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I Ks channel - a tetrameric potassium channel complex formed by K V 7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I Ks channel and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I Ks channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

DOI: https://doi.org/10.1101/2023.01.12.523777