bims-mimbat 2023-08-20 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023–08–20
eight papers selected by
José Carlos de Lima-Júnior, Washington University

Glutamine production by Glul promotes thermogenic adipocyte differentiation through Prdm9-mediated H3K4me3 and transcriptional reprogramming.
Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport.
Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.
Model of membrane deformations driven by a surface pH gradient.
Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.
A sex-specific thermogenic neurocircuit induced by predator smell recruiting cholecystokinin neurons in the dorsomedial hypothalamus.
A parabrachial-hypothalamic parallel circuit governs cold defense in mice.
IF1 promotes oligomeric assemblies of sluggish ATP synthase and outlines the heterogeneity of the mitochondrial membrane potential.

Diabetes. 2023 Aug 14. pii: db230162. [Epub ahead of print]

Glutamine production by Glul promotes thermogenic adipocyte differentiation through Prdm9-mediated H3K4me3 and transcriptional reprogramming.

Xiaowen Pan, Lingxia Ye, Xiaozhen Guo, Weihua Wang, Ziyin Zhang, Qintao Wang, Jingjing Huang, Jingya Xu, Yanhan Cai, Xinxin Shou, Yuting Wang, Yu Feng, Cen Xie, Pengfei Shan, Zhuo-Xian Meng.

Thermogenic adipocytes have been extensively investigated due to their energy dissipating property and therapeutic potential for obesity and diabetes. Besides serving as fuel sources, accumulating evidence suggests that intermediate metabolites play critical roles in multiple biological processes. However, their role in adipocyte differentiation and thermogenesis remains unexplored. Here, we report that human and mouse obesity is associated with marked downregulation of glutamine synthetase (Glul) expression and activity in thermogenic adipose tissues. Glul is robustly upregulated during brown adipocyte (BAC) differentiation and in brown adipose tissue (BAT) upon cold exposure and Cl316,243 stimulation. Further genetic, pharmacologic, or metabolic manipulations of Glul and glutamine levels reveal that glutamine cell-autonomously stimulates BAC differentiation and function, BAT tissue remodeling, and improves systemic energy homeostasis in mice. Mechanistically, glutamine promotes transcriptional induction of adipogenic and thermogenic gene programs through histone modification-mediated chromatin remodeling. Among all the glutamine-regulated writer and eraser genes responsible for histone methylation and acetylation, only Prdm9, a histone lysine methyltransferase, is robustly induced during BAC differentiation. Importantly, Prdm9 inactivation by shRNA knockdown or a selective inhibitor attenuates glutamine-triggered adipogenic and thermogenic induction. Further, Prdm9 gene transcription is regulated by glutamine through the recruitment of C/EBPb to its enhancer region. This work reveals glutamine as a novel activator of thermogenic adipocyte differentiation and uncovers an unexpected role of C/EBPb-Prdm9-mediated H3K4me3 and transcriptional reprogramming in adipocyte differentiation and thermogenesis.

DOI: https://doi.org/10.2337/db23-0162
EMBO Rep. 2023 Aug 14. e56596

Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport.

Shivansh Goyal, Akhilesh Paspureddi, Mu-Jie Lu, Hsin-Ru Chan, Scott N Lyons, Crystal N Wilson, Marc Niere, Mathias Ziegler, Xiaolu A Cambronne.

  SLC25A51 is a member of the mitochondrial carrier family (MCF) but lacks key residues that contribute to the mechanism of other nucleotide MCF transporters. Thus, how SLC25A51 transports NAD+ across the inner mitochondrial membrane remains unclear. To elucidate its mechanism, we use Molecular Dynamics simulations to reconstitute SLC25A51 homology models into lipid bilayers and to generate hypotheses to test. We observe spontaneous binding of cardiolipin phospholipids to three distinct sites on the exterior of SLC25A51's central pore and find that mutation of these sites impairs cardiolipin binding and transporter activity. We also observe that stable formation of the required matrix gate is controlled by a single salt bridge. We identify binding sites in SLC25A51 for NAD+ and show that its selectivity for NAD+ is guided by an electrostatic interaction between the charged nicotinamide ring in the ligand and a negatively charged patch in the pore. In turn, interaction of NAD+ with interior residue E132 guides the ligand to dynamically engage and weaken the salt bridge gate, representing a ligand-induced initiation of transport.

Keywords:  MCART1; SLC25A51; mitochondrial carrier family; mitochondrial transport; nicotinamide adenine dinucleotide (NAD)

DOI:  https://doi.org/10.15252/embr.202256596
bioRxiv. 2023 Aug 02. pii: 2023.05.12.540609. [Epub ahead of print]

Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.

Amber Crabtree, Kit Neikirk, Andrea G Marshall, Larry Vang, Aaron J Whiteside, Qiana Williams, Christopher T Altamura, Trinity Celeste Owens, Dominique Stephens, Bryanna Shao, Alice Koh, Mason Killion, Edgar Garza Lopez, Jacob Lam, Ben Rodriguez, Margaret Mungai, Jade Stanley, E Danielle Dean, Ho-Jin Koh, Jennifer A Gaddy, Estevão Scudese, Mariya Sweetwyne, Jamaine Davis, Elma Zaganjor, Sandra A Murray, Prasanna Katti, Steven M Damo, Zer Vue, Antentor Hinton.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that significant morphological changes in BAT mitochondria and cristae would be present with aging. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.
Abstract Figure:

DOI: https://doi.org/10.1101/2023.05.12.540609
Phys Rev E. 2023 Jul;108(1-1): 014113

Model of membrane deformations driven by a surface pH gradient.

Toni V Mendes, Jonas Ranft, Hélène Berthoumieux.

Many cellular organelles are membrane-bound structures with complex membrane composition and shape. Their shapes have been observed to depend on the metabolic state of the organelle and the mechanisms that couple biochemical pathways and membrane shape are still actively investigated. Here, we study a model coupling inhomogeneities in the lipid composition and membrane geometry via a generalized Helfrich free energy. We derive the resulting stress tensor, the Green's function for a tubular membrane, and compute the phase diagram of the induced deformations. We then apply this model to study the deformation of mitochondria cristae described as membrane tubes supporting a pH gradient at its surface. This gradient in turn controls the lipid composition of the membrane via the protonation or deprotonation of cardiolipins, which are acid-based lipids known to be crucial for mitochondria shape and functioning. Our model predicts the appearance of tube deformations resembling the observed shape changes of cristea when submitted to a proton gradient.

DOI: https://doi.org/10.1103/PhysRevE.108.014113
Nature. 2023 Aug 16.

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.

Neeraj K Lal, Phuong Le, Samarth Aggarwal, Alan Zhang, Kristina Wang, Tianbo Qi, Zhengyuan Pang, Dong Yang, Victoria Nudell, Gene W Yeo, Alexander S Banks, Li Ye.

Maintaining body temperature is calorically expensive for endothermic animals1. Mammals eat more in the cold to compensate for energy expenditure2, but the neural mechanism underlying this coupling is not well understood. Through behavioural and metabolic analyses, we found that mice dynamically switch between energy-conservation and food-seeking states in the cold, the latter of which are primarily driven by energy expenditure rather than the sensation of cold. To identify the neural mechanisms underlying cold-induced food seeking, we used whole-brain c-Fos mapping and found that the xiphoid (Xi), a small nucleus in the midline thalamus, was selectively activated by prolonged cold associated with elevated energy expenditure but not with acute cold exposure. In vivo calcium imaging showed that Xi activity correlates with food-seeking episodes under cold conditions. Using activity-dependent viral strategies, we found that optogenetic and chemogenetic stimulation of cold-activated Xi neurons selectively recapitulated food seeking under cold conditions whereas their inhibition suppressed it. Mechanistically, Xi encodes a context-dependent valence switch that promotes food-seeking behaviours under cold but not warm conditions. Furthermore, these behaviours are mediated by a Xi-to-nucleus accumbens projection. Our results establish Xi as a key region in the control of cold-induced feeding, which is an important mechanism in the maintenance of energy homeostasis in endothermic animals.

DOI: https://doi.org/10.1038/s41586-023-06430-9
Nat Commun. 2023 Aug 15. 14(1): 4937

A sex-specific thermogenic neurocircuit induced by predator smell recruiting cholecystokinin neurons in the dorsomedial hypothalamus.

Predrag Jovanovic, Allan-Hermann Pool, Nancy Morones, Yidan Wang, Edward Novinbakht, Nareg Keshishian, Kaitlyn Jang, Yuki Oka, Celine E Riera.

Olfactory cues are vital for prey animals like rodents to perceive and evade predators. Stress-induced hyperthermia, via brown adipose tissue (BAT) thermogenesis, boosts physical performance and facilitates escape. However, many aspects of this response, including thermogenic control and sex-specific effects, remain enigmatic. Our study unveils that the predator odor trimethylthiazoline (TMT) elicits BAT thermogenesis, suppresses feeding, and drives glucocorticoid release in female mice. Chemogenetic stimulation of olfactory bulb (OB) mitral cells recapitulates the thermogenic output of this response and associated stress hormone corticosterone release in female mice. Neuronal projections from OB to medial amygdala (MeA) and dorsomedial hypothalamus (DMH) exhibit female-specific cFos activity toward odors. Cell sorting and single-cell RNA-sequencing of DMH identify cholecystokinin (CCK)-expressing neurons as recipients of predator odor cues. Chemogenetic manipulation and neuronal silencing of DMHCCK neurons further implicate these neurons in the propagation of predator odor-associated thermogenesis and food intake suppression, highlighting their role in female stress-induced hyperthermia.

DOI: https://doi.org/10.1038/s41467-023-40484-7
Nat Commun. 2023 Aug 15. 14(1): 4924

A parabrachial-hypothalamic parallel circuit governs cold defense in mice.

Wen Z Yang, Hengchang Xie, Xiaosa Du, Qian Zhou, Yan Xiao, Zhengdong Zhao, Xiaoning Jia, Jianhui Xu, Wen Zhang, Shuang Cai, Zhangjie Li, Xin Fu, Rong Hua, Junhao Cai, Shuang Chang, Jing Sun, Hongbin Sun, Qingqing Xu, Xinyan Ni, Hongqing Tu, Ruimao Zheng, Xiaohong Xu, Hong Wang, Yu Fu, Liming Wang, Xi Li, Haitao Yang, Qiyuan Yao, Tian Yu, Qiwei Shen, Wei L Shen.

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.

DOI: https://doi.org/10.1038/s41467-023-40504-6
Commun Biol. 2023 08 12. 6(1): 836

IF1 promotes oligomeric assemblies of sluggish ATP synthase and outlines the heterogeneity of the mitochondrial membrane potential.

Inés Romero-Carramiñana, Pau B Esparza-Moltó, Sonia Domínguez-Zorita, Cristina Nuevo-Tapioles, José M Cuezva.

The coexistence of two pools of ATP synthase in mitochondria has been largely neglected despite in vitro indications for the existence of reversible active/inactive state transitions in the F1-domain of the enzyme. Herein, using cells and mitochondria from mouse tissues, we demonstrate the existence in vivo of two pools of ATP synthase: one active, the other IF1-bound inactive. IF1 is required for oligomerization and inactivation of ATP synthase and for proper cristae formation. Immunoelectron microscopy shows the co-distribution of IF1 and ATP synthase, placing the inactive "sluggish" ATP synthase preferentially at cristae tips. The intramitochondrial distribution of IF1 correlates with cristae microdomains of high membrane potential, partially explaining its heterogeneous distribution. These findings support that IF1 is the in vivo regulator of the active/inactive state transitions of the ATP synthase and suggest that local regulation of IF1-ATP synthase interactions is essential to activate the sluggish ATP synthase.

DOI: https://doi.org/10.1038/s42003-023-05214-1