bims-mimcad 2024-12-08 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–12–08
seven papers selected by
Henver Brunetta, Karolinska Institutet

Blocking adipocyte YY1 decouples thermogenesis from beneficial metabolism by promoting spermidine production.
Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
Expression of p53 in human adipose tissue correlates positively with FAS and BMI.
ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.
Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.
Coordination of cytochrome bc1 complex assembly at MICOS.
LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.

Diabetes. 2024 Dec 02. pii: db240501. [Epub ahead of print]

Blocking adipocyte YY1 decouples thermogenesis from beneficial metabolism by promoting spermidine production.

Chen Qiu, Yu Lu, Suyang Wu, Wenli Guo, Jiahao Ni, Jiyuan Song, Zichao Liu, Xiaoai Chang, Kai Wang, Peng Sun, Qian Zhang, Shufang Yang, Kai Li.

The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the present study, non-biased sequencing-based screening revealed the importance of YY1 in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, adipocyte YY1 null (YAKO) mice showed lower energy expenditure and were intolerant to cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced metabolic disorders, which can be attributed to a suppression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 directed glucose metabolism toward lactate, enhanced the uptake of glutamine, and promoted the production of anti-inflammatory spermidine. Conversely, blocking spermidine production in YAKO mice reversed their resistance to HFD-induced disorders. Thus, although blocking adipocyte YY1 impairs the thermogenesis, it promotes spermidine production and alleviates adipose tissue inflammation, therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders.

DOI: https://doi.org/10.2337/db24-0501
Aging Cell. 2024 Dec 04. e14386

Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.

Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Brent Appelman, Michèle van Vugt, Anita E Grootemaat, Nicole N van der Wel, Jos J de Koning, Frank W Bloemers, Rob C I Wüst.

  Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals. Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2.s-1.mg-1, p = 0.95) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%, p = 0.25), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U., p < 0.0001), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%, p = 0.002) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%, p = 0.005). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density. Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.

Keywords:  ageing; maximal oxygen uptake; mitochondrial morphology; mitochondrial respiration; skeletal muscle

DOI:  https://doi.org/10.1111/acel.14386
Int J Obes (Lond). 2024 Dec 01.

Expression of p53 in human adipose tissue correlates positively with FAS and BMI.

Stephan Wueest, Chiara Scaffidi, Pim P van Krieken, Nils K Konrad, Christian Koch, Ioannis G Lempesis, Jonas Fullin, Konstantinos N Manolopoulos, Steffen Böttcher, Gijs H Goossens, Matthias Blüher, Daniel Konrad.

Activation of Fas (CD95) in adipocytes inhibits browning and may contribute to body weight gain in mice. Moreover, Fas expression in white adipose tissue (WAT) correlates positively with body mass index (BMI) in humans. However, molecular pathways involved in the inhibitory effect of Fas on energy metabolism remain incompletely understood. Herein, we report that protein levels of the tumor suppressor p53 were reduced in primary white adipocytes of adipocyte-specific Fas-knockout mice. Moreover, Fas ligand (FasL) treatment increased p53 concentrations in cultured adipocytes and decreased mitochondrial oxygen consumption in control but not in p53-depleted cells, indicating that Fas activation reduces energy expenditure in a p53-dependent manner. In line, in differentiated human mesenchymal stem cells and WAT derived from different anatomical depots, FAS expression was positively associated with p53. Furthermore, p53 expression in human subcutaneous and visceral WAT correlated positively with BMI, whereas its expression in visceral WAT was inversely associated with insulin sensitivity (as assessed by hyperinsulinemic-euglycemic clamp). Taken together, our data suggest that Fas regulates p53 expression in adipocytes, and may thereby affect body weight gain and insulin sensitivity.

DOI: https://doi.org/10.1038/s41366-024-01691-4
Sci Signal. 2024 Dec 03. 17(865): eadk7971

ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.

Xu Xu, Arturo Mendoza, Christopher S Krumm, Shi Su, Mariana Acuña, Curtis J Bare, Corey D Holman, Marissa Cortopassi, Hayley T Nicholls, Vincent Dartigue, Anthony N Hollenberg, Ann-Hwee Lee, Susan J Hagen, David E Cohen.

Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess. Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct cytoplasmic and nuclear activities. Targeted inhibition of Them1 could be a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.

DOI: https://doi.org/10.1126/scisignal.adk7971
FASEB J. 2024 Dec 15. 38(23): e70223

Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.

Jessica Silver, Adam J Trewin, Stella Loke, Larry Croft, Mark Ziemann, Megan Soria, Hayley Dillon, Søren Nielsen, Séverine Lamon, Glenn D Wadley.

Mitochondria are central to cellular function, particularly in metabolically active tissues such as skeletal muscle. Nuclear-encoded RNAs typically localize within the nucleus and cytosol but a small population may also translocate to subcellular compartments such as mitochondria. We aimed to investigate the nuclear-encoded RNAs that localize within the mitochondria of skeletal muscle cells and tissue. Intact mitochondria were isolated via immunoprecipitation (IP) followed by enzymatic treatments (RNase-A and proteinase-K) optimized to remove transcripts located exterior to mitochondria, making it amenable for high-throughput transcriptomic sequencing. Small RNA sequencing libraries were successfully constructed from as little as 1.8 ng mitochondrial RNA input. Small RNA sequencing of mitochondria from rat myoblasts revealed the enrichment of over 200 miRNAs. Whole-transcriptome RNA sequencing of enzymatically purified mitochondria isolated by IP from skeletal muscle tissue showed a striking similarity in the degree of purity compared to mitoplast preparations which lack an outer mitochondrial membrane. In summary, we describe a novel, powerful sequencing approach applicable to animal and human tissues and cells that can facilitate the discovery of nuclear-encoded RNA transcripts localized within skeletal muscle mitochondria.

DOI: https://doi.org/10.1096/fj.202401618R
EMBO Rep. 2024 Dec 02.

Coordination of cytochrome bc1 complex assembly at MICOS.

Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.

  The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.

Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain

DOI:  https://doi.org/10.1038/s44319-024-00336-x
Obesity (Silver Spring). 2024 Dec 04.

LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.

Jessica Aparecida da Silva Pereira, Gerson Profeta de Souza, João V Virgilio-da-Silva, Juliana S Prodonoff, Gisele de Castro, Leonardo F Pimentel, Felippe Mousovich-Neto, Gustavo G Davanzo, Cristhiane F Aguiar, Cristiane N S Breda, Marcia G Guereschi, Ronaldo C Araújo, Marcelo A Mori, Niels O S Câmara, Diorge P Souza, Alexandre S Basso, Pedro M Moraes-Vieira.

OBJECTIVE: Liver X receptors (LXRs) play essential roles in cholesterol homeostasis and immune response. In obesity, elevated cholesterol levels trigger proinflammatory responses; however, the specific contributions of LXRs to adipose tissue (AT) macrophage (ATM) phenotype and metabolic programming are not fully understood. In this study, we determine the role of LXR isoforms in diet-induced obesity AT inflammation and insulin resistance.
METHODS: For in vivo studies, to evaluate the effects of LXR activation on AT inflammation, obese and insulin-resistant wild-type mice were treated with 10 mg/kg of the LXR modulator naringenin (NAR) for 4 weeks, and systemic insulin sensitivity and AT inflammation were assessed. To evaluate the effects of LXR deficiency on AT inflammation, we used LXRα, LXRβ, and LXRαβ knockout (KO) mice. For in vitro studies, to assess the role of LXRs specifically in macrophages, bone marrow-derived macrophages from wild-type, LXRαKO, LXRβKO, and LXRαβKO mice were treated with 0.5μM NAR 1 h prior to lipopolysaccharide (LPS) stimulation (100 ng/mL), and the effects on macrophage function and metabolism were evaluated 24 h after LPS stimulation.
RESULTS: We found that LXR deletion intensifies AT inflammation in an LXRβ-dependent manner. LXR deficiency in immune cells exacerbates obesity-induced AT inflammation, increasing the numbers of CD11c+, TNF-α+, and IL-1β+ ATMs. We also identified NAR as a novel LXR agonist in macrophages that reduces proinflammatory cytokine secretion by mitigating glycolysis and mitochondrial dysfunction in LPS - and LPS + IFNγ-activated macrophages. Furthermore, NAR-treated obese mice display reduced AT inflammation, characterized by decreased CD11c+, IL-1β+, and TNF-α+ ATM numbers and monocyte infiltration compared with vehicle-treated obese mice.
CONCLUSIONS: Our study highlights distinct roles for each LXR isoform in AT inflammation regulation, with LXRβ being crucial for maintaining the anti- and proinflammatory balance in ATMs. Thus, LXRβ holds therapeutic potential as a target to treat AT inflammation and insulin resistance.

DOI: https://doi.org/10.1002/oby.24158