bims-mimbat 2024-01-28 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒01‒28
ten papers selected by
José Carlos de Lima-Júnior, Washington University

Parallel control of cold-triggered adipocyte thermogenesis by UCP1 and CKB.
Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.
Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.
Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.
Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.
Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.
Brown adipose Vanin-1 is required for the maintenance of mitochondrial homeostasis and prevents diet-induced metabolic dysfunction.
Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
Shared structural features of Miro binding control mitochondrial homeostasis.
Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning.

Cell Metab. 2024 Jan 17. pii: S1550-4131(24)00001-9. [Epub ahead of print]

Parallel control of cold-triggered adipocyte thermogenesis by UCP1 and CKB.

Janane F Rahbani, Jakub Bunk, Damien Lagarde, Bozena Samborska, Anna Roesler, Haopeng Xiao, Abhirup Shaw, Zafir Kaiser, Jessica L Braun, Mia S Geromella, Val A Fajardo, Robert A Koza, Lawrence Kazak.

  That uncoupling protein 1 (UCP1) is the sole mediator of adipocyte thermogenesis is a conventional viewpoint that has primarily been inferred from the attenuation of the thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue. To mitigate these potentially confounding ancillary changes, we constructed mice with inducible adipocyte-selective Ucp1 disruption. We find that, although germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with the inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase b (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold intolerance. Following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature brown adipocytes that coordinately restore UCP1 and CKB expression. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy-through UCP1 and CKB-to promote cold-induced energy dissipation.

Keywords:  adipogenesis; body temperature; brown adipose tissue; cold; creatine kinase b; energy expenditure; inducible; parallel; thermogenesis; uncoupling protein 1

DOI:  https://doi.org/10.1016/j.cmet.2024.01.001
Elife. 2024 Jan 22. pii: e84282. [Epub ahead of print]13

Phosphate starvation signaling increases mitochondrial membrane potential through respiration-independent mechanisms.

Yeyun Ouyang, Mi-Young Jeong, Corey N Cunningham, Jordan A Berg, Ashish G Toshniwal, Casey E Hughes, Kristina Seiler, Jonathan G Van Vranken, Ahmad A Cluntun, Geanette Lam, Jacob M Winter, Emel Akdoǧan, Katja K Dove, Sara M Nowinski, Matthew West, Greg Odorizzi, Steven P Gygi, Cory D Dunn, Dennis R Winge, Jared Rutter.

  Mitochondrial membrane potential directly powers many critical functions of mitochondria, including ATP production, mitochondrial protein import, and metabolite transport. Its loss is a cardinal feature of aging and mitochondrial diseases, and cells closely monitor membrane potential as an indicator of mitochondrial health. Given its central importance, it is logical that cells would modulate mitochondrial membrane potential in response to demand and environmental cues, but there has been little exploration of this question. We report that loss of the Sit4 protein phosphatase in yeast increases mitochondrial membrane potential, both through inducing the electron transport chain and the phosphate starvation response. Indeed, a similarly elevated mitochondrial membrane potential is also elicited simply by phosphate starvation or by abrogation of the Pho85-dependent phosphate sensing pathway. This enhanced membrane potential is primarily driven by an unexpected activity of the ADP/ATP carrier. We also demonstrate that this connection between phosphate limitation and enhancement of mitochondrial membrane potential is observed in primary and immortalized mammalian cells as well as in Drosophila. These data suggest that mitochondrial membrane potential is subject to environmental stimuli and intracellular signaling regulation and raise the possibility for therapeutic enhancement of mitochondrial function even in defective mitochondria.

Keywords:  D. melanogaster; S. cerevisiae; cell biology; human

DOI:  https://doi.org/10.7554/eLife.84282
Cell Rep Med. 2024 Jan 18. pii: S2666-3791(23)00616-X. [Epub ahead of print] 101387

Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.

Lucas Jurado-Fasoli, Guillermo Sanchez-Delgado, Xinyu Di, Wei Yang, Isabelle Kohler, Francesc Villarroya, Concepcion M Aguilera, Thomas Hankemeier, Jonatan R Ruiz, Borja Martinez-Tellez.

  Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.

Keywords:  adiposity; bioactive lipids; brown adipose tissue; cardiometabolic health; cold; endocannabinoids; lipidomics; obesity; oxylipins; polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.xcrm.2023.101387
bioRxiv. 2024 Jan 01. pii: 2023.12.31.573776. [Epub ahead of print]

Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.

Anthony R P Verkerke, Xu Shi, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.

Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo . We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival.Key points: SLC25A48 is required for mitochondrial choline uptake.Mitochondrial choline uptake regulates one-carbon contribution to purine nucleotide synthesis.Brown fat thermogenesis requires mitochondrial choline catabolism for respiratory capacity.Cancer cells require mitochondrial choline uptake for cell survival.

DOI: https://doi.org/10.1101/2023.12.31.573776
bioRxiv. 2024 Jan 07. pii: 2024.01.05.574415. [Epub ahead of print]

Connexin43 in mesenchymal lineage cells regulates body adiposity and energy metabolism in mice.

Seung-Yon Lee, Francesca Fontana, Toshifumi Sugatani, Ignacio Portales Castillo, Giulia Leanza, Ariella Coler-Reilly, Roberto Civitelli.

Connexin43 (Cx43) is the most abundant gap junction protein present in the mesenchymal lineage. In mature adipocytes, Cx43 mediates white adipose tissue (WAT) "beiging" in response to cold exposure and maintains the mitochondrial integrity of brown adipose tissue (BAT). We found that genetic deletion of Gja1 (Cx43 gene) in cells that give rise to chondro-osteogenic and adipogenic precursors driven by the Dermo1/Twist2 promoter leads to lower body adiposity and partial protection against the weight gain and metabolic syndrome induced by a high fat diet (HFD) in both sexes. These protective effects from obesogenic diet are related to increased locomotion, fuel utilization, energy expenditure, non-shivering thermogenesis, and better glucose tolerance in conditionally Gja1 ablated mice. Accordingly, Gja1 mutant mice exhibit reduced adipocyte hypertrophy, partially preserved insulin sensitivity, increased BAT lipolysis and decreased whitening under HFD. This metabolic phenotype is not reproduced with more restricted Gja1 ablation in differentiated adipocytes, suggesting that Cx43 has a hitherto unknown function in adipocyte progenitors or other targeted cells, resulting in restrained energy expenditures and fat accumulation. These results disclose an hitherto unknown action of Cx43 in adiposity, and offer a promising new pharmacologic target for improving metabolic balance in diabetes and obesity.

DOI: https://doi.org/10.1101/2024.01.05.574415
Obesity (Silver Spring). 2024 Jan 22.

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

Andrea Mendez-Gutierrez, Concepcion M Aguilera, Rubén Cereijo, Francisco J Osuna-Prieto, Borja Martinez-Tellez, Maria C Rico, David Sanchez-Infantes, Francesc Villarroya, Jonatan R Ruiz, Guillermo Sanchez-Delgado.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans.METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure.
RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: β = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity.
CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

DOI: https://doi.org/10.1002/oby.23970
Mol Metab. 2024 Jan 19. pii: S2212-8778(24)00015-2. [Epub ahead of print]80 101884

Brown adipose Vanin-1 is required for the maintenance of mitochondrial homeostasis and prevents diet-induced metabolic dysfunction.

Chen Sun, Jiaqi Liang, Jia Zheng, Shuyu Mao, Siyu Chen, Ainiwaer Aikemu, Chang Liu.

  BACKGROUND: Energy-dissipating brown adipocytes have significant potential for improving systemic metabolism. Vanin-1, a membrane-bound pantetheinase, is involved in various biological processes in mice. However, its role in BAT mitochondrial function is still unclear. In this study, we aimed to elucidate the impact of Vanin-1 on BAT function and contribution during overnutrition-induced obesity.METHODS: Vanin-1 expression was analyzed in different adipose depots in mice. The cellular localization of Vanin-1 was analyzed by confocal microscopy and western blots. Mice lacking Vanin-1 (Vanin-1-/-) were continuously fed either a chow diet or a high-fat diet (HFD) to establish an obesity model. RNA-seq analysis was performed to identify the molecular changes associated with Vanin-1 deficiency during obesity. BAT-specific Vanin-1 overexpression mice were established to determine the effects of Vanin-1 in vivo. Cysteamine treatment was used to examine the effect of enzymatic reaction products of Vanin-1 on BAT mitochondria function in Vanin-1-/- mice.
RESULTS: The results indicate that the expression of Vanin-1 is reduced in BAT from both diet-induced and leptin-deficient obese mice. Study on the subcellular location of Vanin-1 shows that it has a mitochondrial localization. Vanin-1 deficiency results in increased adiposity, BAT dysfunction, aberrant mitochondrial structure, and promotes HFD induced-BAT whitening. This is attributed to the impairment of the electron transport chain (ETC) in mitochondria due to Vanin-1 deficiency, resulting in reduced mitochondrial respiration. Overexpression of Vanin-1 significantly enhances energy expenditure and thermogenesis in BAT, renders mice resistant to diet-induced obesity. Furthermore, treatment with cysteamine rescue the mitochondrial dysfunction in Vanin-1-/- mice.
CONCLUSIONS: Collectively, these findings suggest that Vanin-1 plays a crucial role in promoting mitochondrial respiration to counteract diet-induced obesity, making it a potential therapeutic target for obesity.

Keywords:  BAT; Diet-induced obesity; Electron transport chain; Mitochondrial thermogenesis; Vanin-1

DOI:  https://doi.org/10.1016/j.molmet.2024.101884
bioRxiv. 2024 Jan 13. pii: 2024.01.12.575075. [Epub ahead of print]

Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo Lozoya, Ashley M Brooks, Dagoberto Grenet, Cristina A Nadalutti, Birgitta Ryback, Kai Ting Huang, Prottoy Hasan, Gyӧrgy Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted of ATPIF1 , a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.Highlights: Mitochondria hyperpolarization leads to nuclear DNA hypermethylationDNA methylation regulates expression of mitochondrial and lipid metabolism genesPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization.

DOI: https://doi.org/10.1101/2024.01.12.575075
EMBO J. 2024 Jan 24.

Shared structural features of Miro binding control mitochondrial homeostasis.

Christian Covill-Cooke, Brian Kwizera, Guillermo López-Doménech, Caleb Od Thompson, Ngaam J Cheung, Ema Cerezo, Martin Peterka, Josef T Kittler, Benoît Kornmann.

  Miro proteins are universally conserved mitochondrial calcium-binding GTPases that regulate a multitude of mitochondrial processes, including transport, clearance, and lipid trafficking. The exact role of Miro in these functions is unclear but involves binding to a variety of client proteins. How this binding is operated at the molecular level and whether and how it is important for mitochondrial health, however, remains unknown. Here, we show that known Miro interactors-namely, CENPF, Trak, and MYO19-all use a similar short motif to bind the same structural element: a highly conserved hydrophobic pocket in the first calcium-binding domain of Miro. Using these Miro-binding motifs, we identified direct interactors de novo, including MTFR1/2/1L, the lipid transporters Mdm34 and VPS13D, and the ubiquitin E3-ligase Parkin. Given the shared binding mechanism of these functionally diverse clients and its conservation across eukaryotes, we propose that Miro is a universal mitochondrial adaptor coordinating mitochondrial health.

Keywords:  AlphaFold; ERMES; Lipid Transport; Mitophagy; Organelle Transport

DOI:  https://doi.org/10.1038/s44318-024-00028-1
Life Sci. 2024 Jan 23. pii: S0024-3205(24)00042-0. [Epub ahead of print] 122453

Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning.

Tong Pan, Yen-Mei Lee, Eiki Takimoto, Kazutaka Ueda, Pang-Yen Liu, Hsin-Hsueh Shen.

  AIMS: Post-ovariectomy (OVX) changes in hormones induce obesity and white adipose tissue (WAT) inflammation. Increased energy expenditure via WAT browning is a novel therapeutic strategy for treating obesity. Naringenin (NAR) reduces inflammation and lipogenesis in obesity and attenuates estrogen deficiency-associated metabolic disorders; however, its role in WAT browning remains unclear.MATERIALS AND METHODS: We investigated NAR ability to inhibit estrogen deficiency-associated obesity in vivo using a rat model and in vitro using 3T3-L1 adipocytes.
KEY FINDINGS: NAR significantly decreased the body weight and WAT mass of rats. O2 consumption, CO2 production, and energy expenditure were significantly lower in the OVX group than in the sham group, but NAR treatment reversed these effects of OVX. NAR treatment markedly improved glucose intolerance and lipid profiles as well as leptin, adiponectin, and irisin levels. NAR upregulated markers of browning and mitochondrial biogenesis in inguinal WAT. Moreover, it enhanced markers of mitochondrial fusion and inhibited fission via activating the AMP-activated protein kinase pathway. Similar results were observed in 3T3-L1 adipocytes. Moreover, NAR-induced mitochondrial biogenesis and fusion were suppressed by dorsomorphin (an AMP-activated protein kinase inhibitor).
SIGNIFICANCE: NAR alleviates obesity and metabolic dysfunction through the induction of WAT browning achieved via the modulation of AMP-activated protein kinase-regulated mitochondrial dynamics in WATs. NAR supplementation may therefore represent a potential intervention for preventing postmenopausal adipose tissue dysregulation.

Keywords:  Browning; Inflammation; Mitochondrial dynamics; Naringenin; Ovariectomy; White adipose tissue

DOI:  https://doi.org/10.1016/j.lfs.2024.122453