bims-mimbat 2022-04-10 papers

Issue of 2022‒04‒10
six papers selected by
José Carlos de Lima-Júnior
University of California San Francisco

FASEB Bioadv. 2022 Mar;4(3): 197-210

Membrane potential-dependent regulation of mitochondrial complex II by oxaloacetate in interscapular brown adipose tissue.

Brian D Fink, Adam J Rauckhorst, Eric B Taylor, Liping Yu, William I Sivitz.

Classically, mitochondrial respiration responds to decreased membrane potential (ΔΨ) by increasing respiration. However, we found that for succinate-energized complex II respiration in skeletal muscle mitochondria (unencumbered by rotenone), low ΔΨ impairs respiration by a mechanism culminating in oxaloacetate (OAA) inhibition of succinate dehydrogenase (SDH). Here, we investigated whether this phenomenon extends to far different mitochondria of a tissue wherein ΔΨ is intrinsically low, i.e., interscapular brown adipose tissue (IBAT). Also, to advance our knowledge of the mechanism, we performed isotopomer studies of metabolite flux not done in our previous muscle studies. In additional novel work, we addressed possible ways ADP might affect the mechanism in IBAT mitochondria. UCP1 activity, and consequently ΔΨ, were perturbed both by GDP, a well-recognized potent inhibitor of UCP1 and by the chemical uncoupler carbonyl cyanide m-chlorophenyl hydrazone (FCCP). In succinate-energized mitochondria, GDP increased ΔΨ but also increased rather than decreased (as classically predicted under low ΔΨ) O2 flux. In GDP-treated mitochondria, FCCP reduced potential but also decreased respiration. Metabolite studies by NMR and flux analyses by LC-MS support a mechanism, wherein ΔΨ effects on the production of reactive oxygen alters the NADH/NAD+ ratio affecting OAA accumulation and, hence, OAA inhibition of SDH. We also found that ADP-altered complex II respiration in complex fashion probably involving decreased ΔΨ due to ATP synthesis, a GDP-like nucleotide inhibition of UCP1, and allosteric enzyme action. In summary, complex II respiration in IBAT mitochondria is regulated by UCP1-dependent ΔΨ altering substrate flow through OAA and OAA inhibition of SDH.

Keywords: bioenergetics; brown adipose tissue; metabolism; metabolomics; mitochondria; mitochondrial metabolism; reactive oxygen species (ROS); uncoupling protein

DOI: https://doi.org/10.1096/fba.2021-00137

Circ Res. 2022 Apr 07. 101161CIRCRESAHA121320458

Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise Cardioprotection.

Hang Zhao, Xiyao Chen, Guangyu Hu, Congye Li, Lanyan Guo, Ling Zhang, Fangfang Sun, Yunlong Xia, Wenjun Yan, Ze Cui, Yongzhen Guo, Xiong Guo, Chong Huang, Miaomiao Fan, Shan Wang, Fuyang Zhang, Ling Tao.

RATIONALE: Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined.OBJECTIVE: This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury.
METHODS AND RESULTS: Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targeting Rab27a (a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed by Rab27a silencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg, Map3k5, Map2k7, and Map2k4) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors.
CONCLUSIONS: The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.

Keywords: adipose tissue; exercise; extracellular vesicles; myocardial ischemia; reperfusion

DOI: https://doi.org/10.1161/CIRCRESAHA.121.320458

Am J Physiol Endocrinol Metab. 2022 Apr 04.

Jean Himms-Hagen, D.Phil. (1933-2021): Pioneering research in brown adipose tissue thermogenesis.

Mary-Ellen Harper, Anna Hagen.

Keywords: brown adipose tissue; metabolism; obesity; thermogenesis; thermoregulation

DOI: https://doi.org/10.1152/ajpendo.00066.2022

Cell Metab. 2022 Apr 05. pii: S1550-4131(22)00093-6. [Epub ahead of print]34(4): 564-580.e8

Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.

Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H-M Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita.

Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.

Keywords: CCR4-NOT deadenylase complex; FGF21; GDF15; energy expenditure; food intake; hepatokine; inter-organ communication; mRNA degradation; metabolic syndrome

DOI: https://doi.org/10.1016/j.cmet.2022.03.005

J Am Chem Soc. 2022 Apr 05.

Reverse Electron Transfer by Respiratory Complex I Catalyzed in a Modular Proteoliposome System.

John J Wright, Olivier Biner, Injae Chung, Nils Burger, Hannah R Bridges, Judy Hirst.

Respiratory complex I is an essential metabolic enzyme that uses the energy from NADH oxidation and ubiquinone reduction to translocate protons across an energy transducing membrane and generate the proton motive force for ATP synthesis. Under specific conditions, complex I can also catalyze the reverse reaction, Δp-linked oxidation of ubiquinol to reduce NAD+ (or O2), known as reverse electron transfer (RET). Oxidative damage by reactive oxygen species generated during RET underpins ischemia reperfusion injury, but as RET relies on several converging metabolic pathways, little is known about its mechanism or regulation. Here, we demonstrate Δp-linked RET through complex I in a synthetic proteoliposome system for the first time, enabling complete kinetic characterization of RET catalysis. We further establish the capability of our system by showing how RET in the mammalian enzyme is regulated by the active-deactive transition and by evaluating RET by complex I from several species in which direct assessment has not been otherwise possible. We thus provide new insights into the reversibility of complex I catalysis, an important but little understood mechanistic and physiological feature.

DOI: https://doi.org/10.1021/jacs.2c00274

Biochem Biophys Res Commun. 2022 Mar 24. pii: S0006-291X(22)00458-2. [Epub ahead of print]607 20-27

Lactate dehydrogenase regulates basal glucose uptake in adipocytes.

Tomomi Minemura, Atsunori Fukuhara, Michio Otsuki, Iichiro Shimomura.

Plasma glucose levels are homeostatically regulated within strict boundaries and are maintained through a balance between peripheral glucose uptake and hepatic glucose production. However, little is known about the regulatory mechanism of glucose uptake in adipocytes during fasting. Under fasting conditions, the expression levels of 8 glycolytic enzymes were significantly reduced in adipose tissue. Among them, we focused on lactate dehydrogenase A (LDHA), the last enzyme of the glycolytic pathway. Under fasting conditions, both LDHA and Glut1 protein levels tended to decrease in adipose tissue. To elucidate the significance of LDHA in adipocytes, we generated adipocyte-specific LDHA knockout mice (AdLDHAKO) for the first time. AdLDHAKO mice showed no apparent changes in body weight or tissue weight. Under fasting conditions, AdLDHAKO mice exhibited a significant reduction in Glut1 protein levels and glucose uptake in adipose tissues compared with control mice. Similarly, siRNA of LDHA in 3T3-L1 adipocytes reduced Glut1 protein levels and basal glucose uptake. Moreover, treatment with bafilomycin A1, an inhibitor of lysosomal protein degradation, restored Glut1 protein levels by siRNA of LDHA. These results indicate that LDHA regulates Glut1 expression and basal glucose uptake in adipocytes.

Keywords: Adipocyte; Glucose transporter-1; Glycolysis; Insulin; Lactate dehydrogenase

DOI: https://doi.org/10.1016/j.bbrc.2022.03.113