bims-mimbat 2025-03-16 papers

Sci Signal. 2025 Mar 11. 18(877): eadl6441

Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function.

Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen.

Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6 deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6 deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure-induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6 deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.

DOI: https://doi.org/10.1126/scisignal.adl6441

J Cell Sci. 2025 Mar 13. pii: jcs.263693. [Epub ahead of print]

A dual-purification system to isolate mitochondrial subpopulations.

Corey N Cunningham, Jonathan G Van Vranken, Jakeline Larios, Katarina Heyden, Steven P Gygi, Jared Rutter.

Mitochondria perform diverse functions, such as producing ATP through oxidative phosphorylation, synthesizing macromolecule precursors, maintaining redox balance, and many others. Given this diversity of functions, we and others have hypothesized that cells maintain specialized subpopulations of mitochondria. To begin addressing this hypothesis, we developed a new dual-purification system to isolate subpopulations of mitochondria for chemical and biochemical analyses. We used APEX2 proximity labeling such that mitochondria were biotinylated based on proximity to another organelle. All mitochondria were isolated by an elutable MitoTag-based affinity precipitation system. Biotinylated mitochondria were then purified using immobilized avidin. We used this system to compare the proteomes of endosome- and lipid droplet-associated mitochondria in U-2 OS cells, which demonstrated that these subpopulations were indistinguishable from one another but were distinct from the global mitochondria proteome. Our results suggest that this purification system could aid in describing subpopulations that contribute to intracellular mitochondrial heterogeneity, and that this heterogeneity might be more substantial than previously imagined.

Keywords: Biochemistry; Mitochondria; Proximity Labeling; Purification

DOI: https://doi.org/10.1242/jcs.263693

Nature. 2025 Mar 12.

Structure and mechanism of the plastid/parasite ATP/ADP translocator.

Huajian Lin, Jian Huang, Tianming Li, Wenjuan Li, Yutong Wu, Tianjiao Yang, Yuwei Nian, Xiang Lin, Jiangqin Wang, Ruiying Wang, Xiaohui Zhao, Nannan Su, Jinru Zhang, Xudong Wu, Minrui Fan.

Adenosine triphosphate (ATP) is the principal energy currency of all living cells1,2. Metabolically impaired obligate intracellular parasites, such as the human pathogens Chlamydia trachomatis and Rickettsia prowazekii, can acquire ATP from their host cells through a unique ATP/adenosine diphosphate (ADP) translocator, which mediates the import of ATP into and the export of ADP and phosphate out of the parasite cells, thus allowing the exploitation of the energy reserves of host cells (also known as energy parasitism). This type of ATP/ADP translocator also exists in the obligate intracellular endosymbionts of protists and the plastids of plants and algae and has been implicated to play an important role in endosymbiosis3-31. The plastid/parasite type of ATP/ADP translocator is phylogenetically and functionally distinct from the mitochondrial ATP/ADP translocator, and its structure and transport mechanism are still unknown. Here we report the cryo-electron microscopy structures of two plastid/parasite types of ATP/ADP translocators in the apo and substrate-bound states. The ATP/ADP-binding pocket is located at the interface between the N and C domains of the translocator, and a conserved asparagine residue within the pocket is critical for substrate specificity. The translocator operates through a rocker-switch alternating access mechanism involving the relative rotation of the two domains as rigid bodies. Our results provide critical insights for understanding ATP translocation across membranes in energy parasitism and endosymbiosis and offer a structural basis for developing drugs against obligate intracellular parasites.

DOI: https://doi.org/10.1038/s41586-025-08743-3

Science. 2025 Mar 13. eadu6445

Structure of human PINK1 at a mitochondrial TOM-VDAC array.

Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.

Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.

DOI: https://doi.org/10.1126/science.adu6445