bims-mimbat 2024-05-12 papers

Issue of 2024‒05‒12
five papers selected by
José Carlos de Lima-Júnior, Washington University

JCI Insight. 2024 May 07. pii: e164771. [Epub ahead of print]

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.

Xin Cui, Qiang Cao, Fenfen Li, Jia Jing, Zhixue Liu, Xiaosong Yang, Gary J Schwartz, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue.

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces, whereas Suv420h2 overexpression significantly increases Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to down-regulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Keywords: Adipose tissue; Metabolism; Obesity; Uncoupling proteins

DOI: https://doi.org/10.1172/jci.insight.164771

Cell Metab. 2024 May 07. pii: S1550-4131(24)00131-1. [Epub ahead of print]36(5): 891-892

Branching out beyond canonical brown adipocyte function.

Helaina Von Bank, Judith Simcox.

Brown adipose tissue has long been functionally characterized as an organ that regulates thermogenesis, body weight set point, and glucose homeostasis. In the May 9, 2024, issue of Cell, Verkerke et al. discover a novel function for brown adipose tissue in processing branched-chain amino acids into antioxidant metabolites that enter the circulation and regulate insulin signaling in the liver.

DOI: https://doi.org/10.1016/j.cmet.2024.04.011

J Lipid Res. 2024 May 08. pii: S0022-2275(24)00064-6. [Epub ahead of print] 100559

Sphingomyelin Is Involved in Regulating UCP1-Mediated Non-Shivering Thermogenesis.

Detian Hu, Houyu Zhang, Zhen Liu, Carlos F Ibáñez, Cai Tie, Meng Xie.

Adipogenesis is one of the major mechanisms for adipose tissue expansion, during which spindle-shaped mesenchymal stem cells commit to the fate of adipocyte precursors and differentiate into round-shaped fat-laden adipocytes. Here, we investigated the lipidomic profile dynamics of ex vivo differentiated brown and white adipocytes derived from the stromal vascular fractions of interscapular brown (iBAT) and inguinal white adipose tissues (iWAT). We showed that sphingomyelin was specifically enriched in terminally differentiated brown adipocytes, but not white adipocytes. In line with this, freshly isolated adipocytes of iBAT showed higher sphingomyelin content than those of iWAT. Upon cold exposure, sphingomyelin abundance in iBAT gradually decreased in parallel with reduced sphingomyelin synthase 1 protein levels. Cold-exposed animals treated with an inhibitor of sphingomyelin hydrolases failed to maintain core body temperature and showed reduced oxygen consumption and iBAT UCP1 levels. Conversely, blockade of sphingomyelin synthetic enzymes resulted in enhanced non-shivering thermogenesis, reflected by elevated body temperature and UCP1 levels. Taken together, our results uncovered a relation between sphingomyelin abundance and fine-tuning of UCP1-mediated non-shivering thermogenesis.

Keywords: UCP1; UPLC-HRMS; adipocyte; adipogenesis; adipose tissue; sphingolipid; sphingomyelin; thermogenesis

DOI: https://doi.org/10.1016/j.jlr.2024.100559

Nat Commun. 2024 May 08. 15(1): 3367

Identification of a family of species-selective complex I inhibitors as potential anthelmintics.

Taylor Davie, Xènia Serrat, Lea Imhof, Jamie Snider, Igor Štagljar, Jennifer Keiser, Hiroyuki Hirano, Nobumoto Watanabe, Hiroyuki Osada, Andrew G Fraser.

Soil-transmitted helminths (STHs) are major pathogens infecting over a billion people. There are few classes of anthelmintics and there is an urgent need for new drugs. Many STHs use an unusual form of anaerobic metabolism to survive the hypoxic conditions of the host gut. This requires rhodoquinone (RQ), a quinone electron carrier. RQ is not made or used by vertebrate hosts making it an excellent therapeutic target. Here we screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require RQ-dependent metabolism. We identify several classes of compounds including a family of species-selective inhibitors of mitochondrial respiratory complex I. These identified complex I inhibitors have a benzimidazole core and we determine key structural requirements for activity by screening 1,280 related compounds. Finally, we show several of these compounds kill adult STHs. We suggest these species-selective complex I inhibitors are potential anthelmintics.

DOI: https://doi.org/10.1038/s41467-024-47331-3

Nat Metab. 2024 May 08.

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.

DOI: https://doi.org/10.1038/s42255-024-01039-2