bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–02–09
ten papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Multi-layer regulation of postprandial triglyceride metabolism in response to acute cold exposure.
  2. Rhodoquinone carries electrons in the mammalian electron transport chain.
  3. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  4. Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.
  5. Metabolomic signatures associated with cold adaptation and seasonal acclimation of Drosophila: profiling of 43 species.
  6. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  7. Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.
  8. A new player in the mammalian electron transport chain.
  9. Diurnal variation in skeletal muscle mitochondrial function dictates time-of-day-dependent exercise capacity.
  10. Time for lipid cell biology.
  1. J Lipid Res. 2025 Jan 30. pii: S0022-2275(25)00011-2. [Epub ahead of print] 100751
    Multi-layer regulation of postprandial triglyceride metabolism in response to acute cold exposure.
    Yiliang Zhang, Shengyang Zhou, Runming Zhao, Chunyu Xiong, Yingzhen Huang, Minzhu Zhang, Yan Wang.
      Triglyceride-rich lipoproteins (TRLs) carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein (VLDL) production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multi-layered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.
    Keywords:  ANGPTL3; ANGPTL8; Brown adipose tissue; Cold exposure; Triglyceride
    DOI:  https://doi.org/10.1016/j.jlr.2025.100751
  2. Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]
    Rhodoquinone carries electrons in the mammalian electron transport chain.
    Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.
      Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
    Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone
    DOI:  https://doi.org/10.1016/j.cell.2024.12.007
  3. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  4. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00526-6. [Epub ahead of print]
    Piezo2 in sensory neurons regulates systemic and adipose tissue metabolism.
    Fabian S Passini, Bavat Bornstein, Sarah Rubin, Yael Kuperman, Sharon Krief, Evi Masschelein, Tevie Mehlman, Alexander Brandis, Yoseph Addadi, Shira Huri-Ohev Shalom, Erik A Richter, Tal Yardeni, Amir Tirosh, Katrien De Bock, Elazar Zelzer.
      Systemic metabolism ensures energy homeostasis through inter-organ crosstalk regulating thermogenic adipose tissue. Unlike the well-described inductive role of the sympathetic system, the inhibitory signal ensuring energy preservation remains poorly understood. Here, we show that, via the mechanosensor Piezo2, sensory neurons regulate morphological and physiological properties of brown and beige fat and prevent systemic hypermetabolism. Targeting runt-related transcription factor 3 (Runx3)/parvalbumin (PV) sensory neurons in independent genetic mouse models resulted in a systemic metabolic phenotype characterized by reduced body fat and increased insulin sensitivity and glucose tolerance. Deletion of Piezo2 in PV sensory neurons reproduced the phenotype, protected against high-fat-diet-induced obesity, and caused adipose tissue browning and beiging, likely driven by elevated norepinephrine levels. Finding that brown and beige fat are innervated by Runx3/PV sensory neurons expressing Piezo2 suggests a model in which mechanical signals, sensed by Piezo2 in sensory neurons, protect energy storage and prevent a systemic hypermetabolic phenotype.
    Keywords:  PIEZO2; Runx3/PV sensory neurons; body composition; brown and beige adipose tissues; glucose tolerance; insulin sensitivity; mechanosensing; metabolic diseases; norepinephrine; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.016
  5. J Exp Biol. 2025 Feb 06. pii: jeb.250076. [Epub ahead of print]
    Metabolomic signatures associated with cold adaptation and seasonal acclimation of Drosophila: profiling of 43 species.
    Martin Moos, Johannes Overgaard, Petr Hůla, Clara Garfiel Byrge, Petr Šmilauer, Oldřich Nedvěd, Vladimír Koštál.
      Cold tolerance is a key determinant of poleward colonization in insects. However, the physiological basis underlying interspecific differences in cold tolerance is not fully understood. Here, we analyzed cold tolerance and metabolomic profiles in warm- and cold-acclimated phenotypes of 43 Drosophila species representing a latitudinal gradient from the tropics to the boreal zone. We found a strong positive correlation between cold tolerance and climatic variables associated with habitat seasonality and temperature. Including the effects of cold acclimation, we found most species to have similar 'safety margins', measured as the difference between the average environmental temperature and the lower lethal temperature. Searching for metabolomic signatures of cold tolerance, we found that the warm-acclimated flies of cold-hardy species had moderately but significantly higher constitutive signals of putative cryoprotectants such as trehalose, glucose, glycerol, and mannitol/sorbitol. Cold acclimation (and the transition to winter dormant phenotype) resulted in a strong accumulation of myo-inositol, which occurred only in species of the virilis group. Other temperate and boreal species either showed only moderate, idiosyncratic accumulations of sugars/polyols and free amino acids, or did not accumulate any 'classical' cryoprotectant at all. Thus, our results suggest that the colonization of boreal regions by Drosophila does not necessarily depend on the seasonal accumulation of classical cryoprotectants. In contrast, virtually all cold-acclimated species showed a significant increase in products of phospholipid catabolism, suggesting that remodeling of biological membranes is a clear and ubiquitous signature of cold acclimation in Drosophila.
    Keywords:  Acclimation; Climatic zones; Cold tolerance; Cryoprotectants; Insects; Metabolomics
    DOI:  https://doi.org/10.1242/jeb.250076
  6. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  7. Nat Commun. 2025 Feb 04. 16(1): 1330
    Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.
    G V Naveen Kumar, Rui-Sheng Wang, Ankit X Sharma, Natalie L David, Tânia Amorim, Daniel S Sinden, Nandini K Doshi, Martin Wabitsch, Sebastien Gingras, Asim Ejaz, J Peter Rubin, Bradley A Maron, Pouneh K Fazeli, Matthew L Steinhauser.
      Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.
    DOI:  https://doi.org/10.1038/s41467-025-56613-3
  8. Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00494-7. [Epub ahead of print]37(2): 310-312
    A new player in the mammalian electron transport chain.
    Judy Hirst.
      In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.012
  9. FASEB J. 2025 Feb 15. 39(3): e70365
    Diurnal variation in skeletal muscle mitochondrial function dictates time-of-day-dependent exercise capacity.
    Subhash Khatri, Souparno Das, Anshit Singh, Shabbir Ahmad, Mohit Kashiv, Sunil Laxman, Ullas Kolthur-Seetharam.
      Exercise impinges on almost all physiological processes at an organismal level and is a potent intervention to treat various diseases. Exercise performance is well established to display diurnal rhythm, peaking during the late active phase. However, the underlying molecular/metabolic factors and mitochondrial energetics that possibly dictate time-of-day exercise capacity remain unknown. Here, we have unraveled the importance of diurnal variation in mitochondrial functions as a determinant of skeletal muscle exercise performance. Our results show that exercise-induced muscle metabolome and mitochondrial energetics are distinct at ZT3 and ZT15. Importantly, we have elucidated key diurnal differences in mitochondrial functions that are well correlated with disparate time-of-day-dependent exercise capacity. Providing causal mechanistic evidence, we illustrate that loss of Sirtuin4 (SIRT4), a well-known mitochondrial regulator, abrogates mitochondrial diurnal variation and consequently abolishes time-of-day-dependent muscle output. Therefore, our findings unequivocally demonstrate the pivotal role of baseline skeletal muscle mitochondrial functions in dictating diurnal exercise capacity.
    Keywords:  Sirtuin4 (SIRT4); chronobiology; circadian exercise physiology; exercise metabolism; mitochondrial metabolism; skeletal muscle energetics; time‐of‐day exercise capacity
    DOI:  https://doi.org/10.1096/fj.202402930R
  10. Nat Cell Biol. 2025 Feb 05.
    Time for lipid cell biology.
    Xiao-Wei Chen, Anthony S Don, Maria Fedorova, Takeshi Harayama, Natalie Krahmer, Shigekazu Nagata, Priyanka Narayan, Dequina Nicholas, Sara M Nowinski, Yasunori Saheki, Clay F Semenkovich, Xiaoai Zhao, Yilong Zou.
      
    DOI:  https://doi.org/10.1038/s41556-025-01609-w
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