bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2025–02–23
eight papers selected by
Henver Brunetta, Karolinska Institutet
  1. Overfeeding induces adipose tissue release of distinct mitochondria.
  2. RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
  3. An organism-level quantitative flux model of energy metabolism in mice.
  4. adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.
  5. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
  6. Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
  7. Noncoding RNA profiling in omentum adipose tissue from obese patients and the identification of novel metabolic biomarkers.
  8. AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
  1. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318
    Overfeeding induces adipose tissue release of distinct mitochondria.
    Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.
      Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.
    Keywords:  CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.115318
  2. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]
    RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
    Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.
      Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.
    Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
  3. Cell Metab. 2025 Feb 13. pii: S1550-4131(25)00008-7. [Epub ahead of print]
    An organism-level quantitative flux model of energy metabolism in mice.
    Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.
      Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.
    Keywords:  energy metabolism; futile cycle; high-fat diet; isotope tracing; metabolic flux analysis; ob/ob; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.008
  4. Cell Metab. 2025 Feb 14. pii: S1550-4131(25)00012-9. [Epub ahead of print]
    adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.
    Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L Ståhl, Yvonne Böttcher, Maria Keller, Peter Kovacs, Alastair G Kerr, Dominique Langin, Christian Wolfrum, Matthias Blüher, Natalie Krahmer, Lucas Massier, Niklas Mejhert, Mikael Rydén.
      We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.012
  5. Nature. 2025 Feb 19.
    Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
    Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.
      Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
    DOI:  https://doi.org/10.1038/s41586-025-08590-2
  6. J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00155-3. [Epub ahead of print] 108307
    Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
    Hannah M German, Jolita Ciapaite, Nanda M Verhoeven-Duif, Judith J M Jans.
      The constant replenishment of tricarboxylic acid (TCA) cycle intermediates, or anaplerosis, is crucial to ensure optimal TCA cycle activity in times of high biosynthetic demand. In inborn metabolic diseases, anaplerosis is often affected, leading to impaired TCA cycle flux and ATP production. In these cases, anaplerotic compounds can be a therapy option. Triheptanoin, a triglyceride containing three heptanoate chains, is thought to be anaplerotic through production of propionyl- and acetyl-CoA. However, the precise mechanism underlying its anaplerotic action remains poorly understood. In this study, we performed a comprehensive in vitro analysis of heptanoate metabolism and compared it to that of octanoate, an even-chain fatty acid which only provides acetyl-CoA. Using stable isotope tracing, we demonstrate that both heptanoate and octanoate contribute carbon to the TCA cycle in HEK293T cells, confirming direct anaplerosis. Furthermore, by using labeled glucose and glutamine, we show that heptanoate and octanoate decrease the contribution of glucose-derived carbon and increase the influx of glutamine-derived carbon into the TCA cycle. Our findings also point towards a change in redox homeostasis, indicated by an increased NAD+/NADH ratio, accompanied by a decreased lactate/pyruvate ratio and increased de novo serine biosynthesis. Taken together, these results highlight the broad metabolic effects of heptanoate and octanoate supplementation, suggesting that therapeutic efficacy may strongly depend on specific disease pathophysiology. Furthermore, they underline the need for careful selection of fatty acid compound and concentration to optimize anaplerotic action.
    Keywords:  Anaplerosis; fatty acids; isotopic tracer; mass spectrometry (MS); metabolic disease; metabolomics; redox regulation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108307
  7. Front Genet. 2025 ;16 1533637
    Noncoding RNA profiling in omentum adipose tissue from obese patients and the identification of novel metabolic biomarkers.
    Yongjiao Zhang, Ao Chen, Sumei Lu, Dong Liu, Xiaolei Xuan, Xiaofei Lei, Mingwei Zhong, Fei Gao.
       Background: Obesity, a prevalent metabolic disorder, is linked to perturbations in the balance of gene expression regulation. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs), play pivotal roles in regulating gene expression. The aim of this study was to identify additional ncRNA candidates that are implicated in obesity, elucidating their potential as key regulators of the pathogenesis of obesity.
    Methods: We identified distinct ncRNA expression profiles in omental adipose tissue in obese and healthy subjects through comprehensive whole-transcriptome sequencing. Subsequent analyses included functional annotation with GO and KEGG pathway mapping, validation via real-time quantitative polymerase chain reaction (qRT‒PCR), the exploration of protein‒protein interactions (PPIs), and the identification of key regulatory genes through network analysis.
    Results: The results indicated that, compared with those in healthy individuals, various lncRNAs, circRNAs, and miRNAs were significantly differentially expressed in obese subjects. Further verifications of top changed gene expressions proved the most genes' consistence with RNA-sequencing including 11 lncRNAs and 4 circRNAs. Gene network analysis highlighted the most significant features associated with metabolic pathways, specifically ENST00000605862, ENST00000558885, and ENST00000686149. Collectively, our findings suggest potential ncRNA therapeutic targets for obesity, including ENST00000605862, ENST00000558885, and ENST00000686149.
    Keywords:  RNA sequencing (RNA-seq); lncRNA; noncoding RNA (ncRNA); obesity; omental adipose tissue
    DOI:  https://doi.org/10.3389/fgene.2025.1533637
  8. Nat Commun. 2025 Feb 20. 16(1): 1804
    AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
    Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang.
      Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.
    DOI:  https://doi.org/10.1038/s41467-025-57081-5
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