bims-mimbat 2023-08-27 papers

on Mitochondrial metabolism in brown adipose tissue

Issue of 2023‒08‒27
seven papers selected by
José Carlos de Lima-Júnior, Washington University, University of California San Francisco

Multiomics Approaches Identify Biomarkers for BAT Thermogenesis.
HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.
Structural mechanism of mitochondrial membrane remodelling by human OPA1.
Seasonal cold induces divergent structural/biochemical adaptations in different skeletal muscles of Columba livia: Evidence for nonshivering thermogenesis in adult birds.
The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15).
Mitochondrial morphology governs ATP production rate.
OPA1 helical structures give perspective to mitochondrial dysfunction.

J Proteome Res. 2023 Aug 24.

Multiomics Approaches Identify Biomarkers for BAT Thermogenesis.

Li Zhang, Peng Ma, Zijing Wang, Tianshu Xu, Sin Man Lam, Guanghou Shui, Yuzhen Wang, Jiming Xie, Guifen Qiang.

  Brown adipose tissue (BAT) thermogenesis confers beneficial effects on metabolic diseases such as obesity and type-2 diabetes. Nevertheless, the mechanism and lipid driving the process that evokes this response have not been investigated yet. Here, a multiomics approach of integrative transcriptomics and lipidomics is used to explore the mechanism of regulating thermogenesis in BAT and providing promising lipid biomarkers and biomarker genes for thermogenic activators as antiobesity drugs. Lipidomics analysis demonstrated that a high abundance of glycerophospholipids and sphingolipids was more significant in BAT than in WAT. Enrichment analysis of upregulated DEGs between WAT and BAT screened suggested that the differences were mainly involved in lipid metabolism. Besides, β3-adrenergic agonist stimulation reduced the levels of TAG and DAG and increased the content of PC, PE, CL, and LPC and expression of genes involved in thermogenesis, fatty acid elongation, and glycerophospholipid metabolism in BAT. In this study, based on interpreting the inherent characterization of BAT as thermogenic tissue through comparison with WAT as fat storage tissue, adrenergic stimulation-induced BAT thermogenesis further identified specific lipid biomarkers (7 TAG species, 10 PC species, 1 LPC species, and 1 CL species) and Elovl3 and Crat gene biomarkers, which may provide targets for combating obesity by boosting BAT thermogenesis.

Keywords:  brown adipose tissue; lipidomics; thermogenesis; transcriptomics; white adipose tissue

DOI:  https://doi.org/10.1021/acs.jproteome.3c00423
J Clin Invest. 2023 Aug 22. pii: e168192. [Epub ahead of print]

HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.

Emma L Robinson, Rushita Bagchi, Jennifer L Major, Bryan C Bergman, Jennifer L Matsuda, Timothy A McKinsey.

  Stimulation of adipocyte beta-adrenergic receptors (beta-ARs) induces expression of uncoupling protein 1 (UCP1), promoting non-shivering thermogenesis. Association of beta-ARs with a lysine myristoylated form of A-kinase anchoring protein 12 (AKAP12)/gravin-alpha is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-alpha by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of beta-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-alpha myristoylation-dependent induction of UCP1 protein expression, with a non-canonical acute response that is post-transcriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where beta-AR signaling is blocked. These findings define cell autonomous, multi-modal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of beta-AR stimulation.

Keywords:  Adipose tissue; G proteincoupled receptors; Metabolism

DOI:  https://doi.org/10.1172/JCI168192
Nature. 2023 Aug 23.

Structural mechanism of mitochondrial membrane remodelling by human OPA1.

Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.

Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.

DOI: https://doi.org/10.1038/s41586-023-06441-6
Biochem J. 2023 Aug 25. pii: BCJ20230245. [Epub ahead of print]

Seasonal cold induces divergent structural/biochemical adaptations in different skeletal muscles of Columba livia: Evidence for nonshivering thermogenesis in adult birds.

Punyadhara Pani, Gourabamani Swalsingh, Sunil Pani, Unmod Senapati, Bijayashree Sahu, Benudhara Pati, Subhasmita Rout, Naresh C Bal.

  Birds are endothermic homeotherms even though they lack the well-studied heat producing brown adipose tissue (BAT), found in several clades of eutherian mammals. Earlier studies in ducklings have demonstrated that skeletal muscle is the primary organ of nonshivering thermogenesis (NST) plausibly via futile calcium (Ca2+)-handling through ryanodine receptor (RyR) and sarco-endoplasmic reticulum Ca2+-ATPase (SERCA). However, recruitment of futile Ca2+-cycling in adult avian skeletal muscle has not been documented. Studies in mammals show remarkable mitochondrial remodeling concurrently with muscle NST during cold. Here, we wanted to define the mitochondrial and biochemical changes in the muscles in free-ranging adult birds and whether different skeletal muscle groups undergo similar seasonal changes. We analyzed four different muscles (pectoralis, biceps, triceps and iliotibialis) from local pigeon (Columba livia) collected during summer and winter seasons in two consecutive years. Remarkable increase in mitochondrial capacity was observed as evidenced from succinate dehydrogenase (SDH) and cyclooxygenase (COX) activity staining in all the muscles. Interestingly, fibers with low SDH activity exhibited greater cross-sectional area during winter in all muscles except iliotibialis and became peripherally arranged in individual fascicles of pectoralis, which might indicate increased shivering. Further, gene expression analysis showed that SERCA, sarcolipin and RyR are upregulated to different levels in the muscles analyzed indicating muscle NST via futile Ca2+-cycling is recruited to varying degrees in winter. Moreover, proteins of mitochondrial-SR-tethering and biogenesis also showed differential alterations across the muscles. These data suggest that tropical winter (~15°C) is sufficient to induce distinct remodeling across muscles in adult bird.

Keywords:  cold acclimatization; futile Ca2+ cycling; mitochondria; non-shivering thermogenesis; skeletal muscle

DOI:  https://doi.org/10.1042/BCJ20230245
Elife. 2023 Aug 21. pii: e88350. [Epub ahead of print]12

The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15).

Ilja Vietor, Domagoj Cikes, Kati Piironen, Theodora Vasakou, David Heimdörfer, Ronald Gstir, Matthias David Erlacher, Ivan Tancevski, Philipp Eller, Egon Demetz, Michael W Hess, Volker Kuhn, Gerald Degenhart, Jan Rozman, Martin Klingenspor, Martin Hrabe de Angelis, Taras Valovka, Lukas A Huber.

  Delta-like homolog 1 (Dlk1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Experimental data presented here identify two independent regulatory mechanisms, transcriptional and translational, by which Ifrd1 (TIS7) and its orthologue Ifrd2 (SKMc15) regulate Dlk1 levels. Mice deficient in both Ifrd1 and Ifrd2 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk1 inhibited the expression of adipogenesis regulators Pparg and Cebpa, and fatty acid transporter Cd36. Although both, Ifrd1 and Ifrd2, contributed to this phenotype, they utilized two different mechanisms. Ifrd1 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk1. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of Dlk1 regulation in adipocyte differentiation involving Ifrd1 and Ifrd2 are based on experimental data presented here.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.88350
J Gen Physiol. 2023 09 04. pii: e202213263. [Epub ahead of print]155(9):

Mitochondrial morphology governs ATP production rate.

Guadalupe C Garcia, Kavya Gupta, Thomas M Bartol, Terrence J Sejnowski, Padmini Rangamani.

Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work. The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure that the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3-D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.

DOI: https://doi.org/10.1085/jgp.202213263
Nature. 2023 Aug 23.

OPA1 helical structures give perspective to mitochondrial dysfunction.

Sarah B Nyenhuis, Xufeng Wu, Marie-Paule Strub, Yang-In Yim, Abigail E Stanton, Valentina Baena, Zulfeqhar A Syed, Bertram Canagarajah, John A Hammer, Jenny E Hinshaw.

Dominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases1 are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria2. Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes3. Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains-a hallmark of the dynamin superfamily of proteins4. OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions.

DOI: https://doi.org/10.1038/s41586-023-06462-1