bims-mimbat 2023-03-19 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023–03–19
twenty-two papers selected by
José Carlos de Lima-Júnior, Washington University

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
Plasticity of mitochondrial function safeguards phosphorylating respiration during in vitro simulation of rest-phase hypothermia.
SnapShot: Mitochondrial signaling.
The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue.
De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics.
Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice.
Lactate regulates cell cycle by remodeling the anaphase promoting complex.
Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
From the 'black box' to 'domino effect' mechanism: what have we learned from the structures of respiratory complex I.
Adipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice.
Mitochondria: A "pacemaker" for species-specific development.
Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.
Endothelial DLL4 Is an Adipose Depot-Specific Fasting Sensor Regulating Fatty Acid Fluxes.
Impaired adipocyte SLC7A10 promotes lipid storage in association with insulin resistance and altered BCAA metabolism.
Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia.
Intracytoplasmic-membrane development in alphaproteobacteria involves the homolog of the mitochondrial crista-developing protein Mic60.
OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
Omics-based approaches for the systematic profiling of mitochondrial biology.
The fire of evolution: energy expenditure and ecology in primates and other endotherms.
UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.

bioRxiv. 2023 Mar 02. pii: 2023.03.01.530625. [Epub ahead of print]

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.

Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Evanna L Mills, Edward T Chouchani.

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacity in vivo . In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

DOI: https://doi.org/10.1101/2023.03.01.530625
EMBO J. 2023 Mar 14. e111901

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.

Jennifer Ngo, Dong Wook Choi, Illana A Stanley, Linsey Stiles, Anthony J A Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-Young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S Divakaruni, Marc Liesa, Nika N Danial, Orian S Shirihai.

  Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

Keywords:  CPT1; fatty acid oxidation; fission; fusion; mitochondrial dynamics

DOI:  https://doi.org/10.15252/embj.2022111901
EMBO J. 2023 Mar 13. e111699

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.

Rebeca Acin-Perez, Cristiane Benincá, Lucia Fernandez Del Rio, Cynthia Shu, Siyouneh Baghdasarian, Vanessa Zanette, Christoph Gerle, Chimari Jiko, Ramzi Khairallah, Shaharyar Khan, David Rincon Fernandez Pacheco, Byourak Shabane, Karel Erion, Ruchi Masand, Sundeep Dugar, Cristina Ghenoiu, George Schreiner, Linsey Stiles, Marc Liesa, Orian S Shirihai.

  The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.

Keywords:  ATP hydrolysis; ATPase Inhibitor (ATPIF1); Complex V; epicatechin; muscular dystrophy

DOI:  https://doi.org/10.15252/embj.2022111699
FASEB J. 2023 Apr;37(4): e22854

Plasticity of mitochondrial function safeguards phosphorylating respiration during in vitro simulation of rest-phase hypothermia.

Carmen C García-Díaz, Imen Chamkha, Eskil Elmér, Andreas Nord.

  Many animals downregulate body temperature to save energy when resting (rest-phase hypothermia). Small birds that winter at high latitudes have comparatively limited capacity for hypothermia and so pay large energy costs for thermoregulation during cold nights. Available evidence suggests this process is fueled by adenosine triphosphate (ATP)-dependent mechanisms. Most ATP is produced by oxidative phosphorylation in the mitochondria, but mitochondrial respiration may be lower during hypothermia because of the temperature dependence of biological processes. This can create conflict between increased organismal ATP demand and a lower mitochondrial capacity to provide it. We studied this in blood cell mitochondria of wild great tits (Parus major) by simulating rest-phase hypothermia via a 6°C reduction in assay temperature in vitro. The birds had spent the night preceding the experiment in thermoneutrality or in temperatures representing mild or very cold winter nights, but night temperatures never affected mitochondrial respiration. However, across temperature groups, endogenous respiration was 14% lower in hypothermia. This did not reflect general thermal suppression of mitochondrial function because phosphorylating respiration was unaffected by thermal state. Instead, hypothermia was associated with a threefold reduction of leak respiration, from 17% in normothermia to 4% in hypothermia. Thus, the coupling of total respiration to ATP production was 96% in hypothermia, compared to 83% in normothermia. Our study shows that the thermal insensitivity of phosphorylation combined with short-term plasticity of leak respiration may safeguard ATP production when endogenous respiration is suppressed. This casts new light on the process by which small birds endure harsh winter cold and warrants future tests across tissues in vivo.

Keywords:  blood cells; body temperature; cell respiration; great tit; mitochondria; thermoregulation

DOI:  https://doi.org/10.1096/fj.202201613R
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00028-X. [Epub ahead of print]83(6): 1012-1012.e1

SnapShot: Mitochondrial signaling.

Taylor A Poor, Navdeep S Chandel.

Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2023.01.008
Mol Metab. 2023 Mar 11. pii: S2212-8778(23)00039-X. [Epub ahead of print] 101705

The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue.

Gudrun Liebscher, Nemanja Vujic, Renate Schreiber, Markus Heine, Caroline Krebiehl, Madalina Duta-Mare, Giorgia Lamberti, Cedric H de Smet, Michael W Hess, Thomas O Eichmann, Sarah Hölzl, Ludger Scheja, Joerg Heeren, Dagmar Kratky, Lukas A Huber.

   OBJECTIVE: In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive.
METHODS: Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed.
RESULTS: Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs.
CONCLUSIONS: We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.

Keywords:  AKT; Brown adipose tissue; LAMTOR; Lysosome; Ragulator; mTORC1/2

DOI:  https://doi.org/10.1016/j.molmet.2023.101705
Nat Commun. 2023 Mar 13. 14(1): 1362

De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics.

Leslie A Rowland, Adilson Guilherme, Felipe Henriques, Chloe DiMarzio, Sean Munroe, Nicole Wetoska, Mark Kelly, Keith Reddig, Gregory Hendricks, Meixia Pan, Xianlin Han, Olga R Ilkayeva, Christopher B Newgard, Michael P Czech.

Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes.

DOI: https://doi.org/10.1038/s41467-023-37016-8
iScience. 2023 Mar 17. 26(3): 106272

Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice.

Chenguang Wang, Yalan Wu, Yangxian Li, Yang Zhang, Yee Lok Fung, Ka Kui Tong, Chi Wai Lau, Li Xiang, Kin Ming Kwan, Li-Ru You, Yu Huang, Xiao Yu Tian.

  Beige adipocytes are thermogenic with high expression of uncoupling protein 1 in the white adipose tissue (WAT), accompanied by angiogenesis. Previous studies showed that Smad4 is important for angiogenesis. Here we studied whether endothelial Smad4-mediated angiogenesis is involved in WAT beiging. Inducible knockout of endothelial cell (EC) selective Smad4 (Smad4 iEC-KO) was achieved by using the Smad4 Floxp/floxp and Tie2 CreERT2 mice. Beige fat induction achieved by cold or adrenergic agonist, and angiogenesis were attenuated in WAT of Smad4 iEC-KO mice, with the less proliferation of ECs and adipogenic precursors. RNA sequencing of human ECs showed that Smad4 is involved in angiogenesis-related pathways. Knockdown of SMAD4 attenuated the upregulation of VEGFA, PDGFA, and angiogenesis in vitro. Treatment of human ECs with palmitic acid-induced Smad1/5 phosphorylation and the upregulation of core endothelial genes. Our study shows that endothelial Smad4 is involved in WAT beiging through angiogenesis and the expansion of adipose precursors into beige adipocytes.

Keywords:  Biological sciences; Cell biology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.106272
Nature. 2023 Mar 15.

Lactate regulates cell cycle by remodeling the anaphase promoting complex.

Weihai Liu, Yun Wang, Luiz H M Bozi, Patrick Fischer, Mark P Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna L Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z Xu, Luke Sebastian, Jean Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven P Gygi, Haribabu Arthanari, Edward T Chouchani.

Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

DOI: https://doi.org/10.1038/s41586-023-05939-3
EMBO Rep. 2023 Mar 17. e56114

Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.

Reut Hazan Ben-Menachem, Dvora Lintzer, Tamar Ziv, Koyeli Das, Irit Rosenhek-Goldian, Ziv Porat, Hila Ben Ami Pilo, Sharon Karniely, Ann Saada, Neta Regev-Rudzki, Ophry Pines.

  Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.

Keywords:  ATP synthase; membrane potential; mitochondria; mitochondrial-derived vesicles; protein distribution

DOI:  https://doi.org/10.15252/embr.202256114
Biochem J. 2023 Mar 15. 480(5): 319-333

From the 'black box' to 'domino effect' mechanism: what have we learned from the structures of respiratory complex I.

Leonid A Sazanov.

  My group and myself have studied respiratory complex I for almost 30 years, starting in 1994 when it was known as a L-shaped giant 'black box' of bioenergetics. First breakthrough was the X-ray structure of the peripheral arm, followed by structures of the membrane arm and finally the entire complex from Thermus thermophilus. The developments in cryo-EM technology allowed us to solve the first complete structure of the twice larger, ∼1 MDa mammalian enzyme in 2016. However, the mechanism coupling, over large distances, the transfer of two electrons to pumping of four protons across the membrane remained an enigma. Recently we have solved high-resolution structures of mammalian and bacterial complex I under a range of redox conditions, including catalytic turnover. This allowed us to propose a robust and universal mechanism for complex I and related protein families. Redox reactions initially drive conformational changes around the quinone cavity and a long-distance transfer of substrate protons. These set up a stage for a series of electrostatically driven proton transfers along the membrane arm ('domino effect'), eventually resulting in proton expulsion from the distal antiporter-like subunit. The mechanism radically differs from previous suggestions, however, it naturally explains all the unusual structural features of complex I. In this review I discuss the state of knowledge on complex I, including the current most controversial issues.

Keywords:  complex I; electron transfer; membrane protein structure; proton pumping; respiratory chain

DOI:  https://doi.org/10.1042/BCJ20210285
Nat Commun. 2023 Mar 13. 14(1): 1379

Adipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice.

Sujun Yan, Xiaoling Zhou, Canlan Wu, Yunyi Gao, Yu Qian, Jingyu Hou, Renxiang Xie, Bing Han, Zhanghui Chen, Saisai Wei, Xiangwei Gao.

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. N(6)-methyladenosine (m6A) RNA modification has been recently identified as a key regulator of obesity, while the detailed mechanism is elusive. Here, we find that YTH RNA binding protein 1 (YTHDF1), an m6A reader, acts as an essential regulator of white adipose tissue metabolism. The expression of YTHDF1 decreases in adipose tissue of male mice fed a high-fat diet. Adipocyte-specific Ythdf1 deficiency exacerbates obesity-induced metabolic defects and inhibits beiging of inguinal white adipose tissue (iWAT) in male mice. By contrast, male mice with WAT-specific YTHDF1 overexpression are resistant to obesity and shows promotion of beiging. Mechanistically, YTHDF1 regulates the translation of diverse m6A-modified mRNAs. In particular, YTHDF1 facilitates the translation of bone morphogenetic protein 8b (Bmp8b) in an m6A-dependent manner to induce the beiging process. Here, we show that YTHDF1 may be an potential therapeutic target for the management of obesity-associated diseases.

DOI: https://doi.org/10.1038/s41467-023-37100-z
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00152-1. [Epub ahead of print]83(6): 824-826

Mitochondria: A "pacemaker" for species-specific development.

Yasmine J Liu, Johan Auwerx.

We highlight papers by Diaz-Cuadros et al.1 and Iwata et al.2 that demonstrate the role of mitochondrial metabolism in setting developmental pace through their control over cellular bioenergetics and redox homeostasis in mice and humans.

DOI: https://doi.org/10.1016/j.molcel.2023.02.025
J Biol Chem. 2023 Mar 15. pii: S0021-9258(23)00253-3. [Epub ahead of print] 104611

Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.

Greg W Trieger, Ariane R Pessentheiner, Sean C Purcell, Courtney R Green, Natalie DeForest, Karl Willert, Amit R Majithia, Christian M Metallo, Kamil Godula, Philip L S M Gordts.

Adipose tissue (AT) plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like AT become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, modulating the glycocalyx, a layer of cell-surface glycans, is an underexplored pharmacological treatment strategy to improve glucose homeostasis in T2D patients. Here, we show a novel role for cell surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering the glycocalyx of preadipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion.

DOI: https://doi.org/10.1016/j.jbc.2023.104611
Arterioscler Thromb Vasc Biol. 2023 Mar 16.

Endothelial DLL4 Is an Adipose Depot-Specific Fasting Sensor Regulating Fatty Acid Fluxes.

Alex Aupetit, Pauline Decaunes, Chloé Belles, Elodie Riant, Jean Galitzky, Candice Chapouly, Margaux Laisné, Rémy Flores-Flores, Benoit Chaput, Katell Vié, Jean-François Arnal, Anne Bouloumié, Anaïs Briot.

   BACKGROUND: Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fasted state. How AT-EC sense and adapt to metabolic changes according to AT location remains to be established.
METHODS: We combined transcriptional analysis of native human AT-EC together with in vitro approaches in primary human AT-EC and in vivo and ex vivo studies of mice under fed and fasted conditions.
RESULTS: Transcriptional large-scale analysis of human AT-EC isolated from gluteofemoral and abdominal subcutaneous AT revealed that the endothelium exhibits a fat depot-specific signature associated with lipid handling and Notch signaling enrichment. We uncovered a functional link between metabolic status and endothelial DLL4, which decreases with fasting. DLL4 regulates fatty acid uptake through nontranscriptional modulation of macropinocytosis-dependent long chain fatty acid uptake. Importantly, the changes in DLL4 expression, in response to energy transition state, is impaired under obesogenic conditions, an early alteration coinciding with a defect in systemic fatty acid fluxes adaptation and a resistance to weight loss.
CONCLUSIONS: DLL4 is a major actor in the adaptive mechanisms of AT-EC to regulate lipid fluxes. It likely contributes to fat depot-dependent metabolism in response to energy transition states. AT-EC alteration with obesity may favor metabolic inflexibility and the development of cardiometabolic disorders.

Keywords:  adipose; endothelium; lipid; metabolic flexibility; notch signaling

DOI:  https://doi.org/10.1161/ATVBAHA.122.318876
J Clin Endocrinol Metab. 2023 Mar 14. pii: dgad148. [Epub ahead of print]

Impaired adipocyte SLC7A10 promotes lipid storage in association with insulin resistance and altered BCAA metabolism.

Regine Å Jersin, Divya Sri Priyanka Tallapragada, Linn Skartveit, Mona S Bjune, Maheswary Muniandy, Sindre Lee-Ødegård, Sini Heinonen, Marcus Alvarez, Kåre Inge Birkeland, Christian André Drevon, Päivi Pajukanta, Adrian McCann, Kirsi H Pietiläinen, Melina Claussnitzer, Gunnar Mellgren, Simon N Dankel.

   CONTEXT: The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity.
OBJECTIVE: We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites.
DESIGN: In adipocyte cultures with impaired SLC7A10, we performed RNA-sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in two independent cohorts.
RESULTS: SLC7A10 impairment altered expression of genes related to metabolic processes including branched-chain amino acid (BCAA) catabolism, lipogenesis and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased the net uptake of BCAAs, while increasing the net release of the valine catabolite 3-hydroxyisobytsurate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating TAG, BCAAs and 3-HIB.
CONCLUSION: Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB.

Keywords:  Adipocytes; Amino acid metabolism; Branched chain amino acids; Insulin resistance; Lipid storage; Obesity

DOI:  https://doi.org/10.1210/clinem/dgad148
Elife. 2023 Mar 15. pii: e85103. [Epub ahead of print]12

Diet-induced loss of adipose hexokinase 2 correlates with hyperglycemia.

Mitsugu Shimobayashi, Amandine Thomas, Sunil Shetty, Irina C Frei, Bettina K Wölnerhanssen, Diana Weissenberger, Anke Vandekeere, Mélanie Planque, Nikolaus Dietz, Danilo Ritz, Anne Christin Meyer-Gerspach, Timm Maier, Nissim Hay, Ralph Peterli, Sarah-Maria Fendt, Nicolas Rohner, Michael N Hall.

  Chronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here, we show that a high-fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 reduced glucose disposal and lipogenesis and enhanced fatty acid release in adipose tissue. In a non-cell-autonomous manner, Hk2 knockout also promoted glucose production in liver. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of local and systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia.

Keywords:  adipose tissue; astyanax mexicanus; cell biology; diabetes; glucose; human; lipid metabolism; mouse; obesity; selective insulin resistance

DOI:  https://doi.org/10.7554/eLife.85103
Curr Biol. 2023 Mar 08. pii: S0960-9822(23)00199-9. [Epub ahead of print]

Intracytoplasmic-membrane development in alphaproteobacteria involves the homolog of the mitochondrial crista-developing protein Mic60.

Sergio A Muñoz-Gómez, Lawrence Rudy Cadena, Alastair T Gardiner, Michelle M Leger, Shaghayegh Sheikh, Louise B Connell, Tomáš Bilý, Karel Kopejtka, J Thomas Beatty, Michal Koblížek, Andrew J Roger, Claudio H Slamovits, Julius Lukeš, Hassan Hashimi.

  Mitochondrial cristae expand the surface area of respiratory membranes and ultimately allow for the evolutionary scaling of respiration with cell volume across eukaryotes. The discovery of Mic60 homologs among alphaproteobacteria, the closest extant relatives of mitochondria, suggested that cristae might have evolved from bacterial intracytoplasmic membranes (ICMs). Here, we investigated the predicted structure and function of alphaproteobacterial Mic60, and a protein encoded by an adjacent gene Orf52, in two distantly related purple alphaproteobacteria, Rhodobacter sphaeroides and Rhodopseudomonas palustris. In addition, we assessed the potential physical interactors of Mic60 and Orf52 in R. sphaeroides. We show that the three α helices of mitochondrial Mic60's mitofilin domain, as well as its adjacent membrane-binding amphipathic helix, are present in alphaproteobacterial Mic60. The disruption of Mic60 and Orf52 caused photoheterotrophic growth defects, which are most severe under low light conditions, and both their disruption and overexpression led to enlarged ICMs in both studied alphaproteobacteria. We also found that alphaproteobacterial Mic60 physically interacts with BamA, the homolog of Sam50, one of the main physical interactors of eukaryotic Mic60. This interaction, responsible for making contact sites at mitochondrial envelopes, has been conserved in modern alphaproteobacteria despite more than a billion years of evolutionary divergence. Our results suggest a role for Mic60 in photosynthetic ICM development and contact site formation at alphaproteobacterial envelopes. Overall, we provide support for the hypothesis that mitochondrial cristae evolved from alphaproteobacterial ICMs and have therefore improved our understanding of the nature of the mitochondrial ancestor.

Keywords:  Cereibacter; MICOS; Rhodobacter; Rhodopseudomonas; chromatophores; endosymbosis; eukaryogenesis; eukaryote; purple bacteria

DOI:  https://doi.org/10.1016/j.cub.2023.02.059
Proc Natl Acad Sci U S A. 2023 Mar 21. 120(12): e2207471120

OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.

Benjamín Cartes-Saavedra, Daniel Lagos, Josefa Macuada, Duxan Arancibia, Florence Burté, Marcela K Sjöberg-Herrera, María Estela Andrés, Rita Horvath, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.

  Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.

Keywords:  ADOA; OPA1; cristae; dynamics; mitochondria

DOI:  https://doi.org/10.1073/pnas.2207471120
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00118-1. [Epub ahead of print]83(6): 911-926

Omics-based approaches for the systematic profiling of mitochondrial biology.

Jasmin Adriana Schäfer, F X Reymond Sutandy, Christian Münch.

Mitochondria are essential for cellular functions such as metabolism and apoptosis. They dynamically adapt to the changing environmental demands by adjusting their protein, nucleic acid, metabolite, and lipid contents. In addition, the mitochondrial components are modulated on different levels in response to changes, including abundance, activity, and interaction. A wide range of omics-based approaches has been developed to be able to explore mitochondrial adaptation and how mitochondrial function is compromised in disease contexts. Here, we provide an overview of the omics methods that allow us to systematically investigate the different aspects of mitochondrial biology. In addition, we show examples of how these methods have provided new biological insights. The emerging use of these toolboxes provides a more comprehensive understanding of the processes underlying mitochondrial function.

DOI: https://doi.org/10.1016/j.molcel.2023.02.015
J Exp Biol. 2023 Mar 01. pii: jeb245272. [Epub ahead of print]226(5):

The fire of evolution: energy expenditure and ecology in primates and other endotherms.

Amanda McGrosky, Herman Pontzer.

  Total energy expenditure (TEE) represents the total energy allocated to growth, reproduction and body maintenance, as well as the energy expended on physical activity. Early experimental work in animal energetics focused on the costs of specific tasks (basal metabolic rate, locomotion, reproduction), while determination of TEE was limited to estimates from activity budgets or measurements of subjects confined to metabolic chambers. Advances in recent decades have enabled measures of TEE in free-living animals, challenging traditional additive approaches to understanding animal energy budgets. Variation in lifestyle and activity level can impact individuals' TEE on short time scales, but interspecific differences in TEE are largely shaped by evolution. Here, we review work on energy expenditure across the animal kingdom, with a particular focus on endotherms, and examine recent advances in primate energetics. Relative to other placental mammals, primates have low TEE, which may drive their slow pace of life and be an evolved response to the challenges presented by their ecologies and environments. TEE variation among hominoid primates appears to reflect adaptive shifts in energy throughput and allocation in response to ecological pressures. As the taxonomic breadth and depth of TEE data expand, we will be able to test additional hypotheses about how energy budgets are shaped by environmental pressures and explore the more proximal mechanisms that drive intra-specific variation in energy expenditure.

Keywords:  Ecology; Energetics; Environment; Evolution; Trade-off

DOI:  https://doi.org/10.1242/jeb.245272
J Clin Invest. 2023 Mar 15. pii: e169986. [Epub ahead of print]133(6):

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.

Jong-Seok Moon, Seonmin Lee, Mi-Ae Park, Ilias I Siempos, Maria Haslip, Patty J Lee, Mijin Yun, Chun K Kim, Judie Howrylak, Stefan W Ryter, Kiichi Nakahira, Augustine Mk Choi.

DOI: https://doi.org/10.1172/JCI169986