bims-smemid 2025-09-28 papers

Sci Signal. 2025 Sep 23. 18(905): eaec3820

Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.

DOI: https://doi.org/10.1126/scisignal.aec3820

Pflugers Arch. 2025 Sep 27.

Energy metabolism in different skeletal muscles and muscle fibers: implications for injury and dietary supplementation.

Andrey V Kuznetsov, Raimund Margreiter, Judith Hagenbuchner, Michael J Ausserlechner.

The necessary energy supply in skeletal muscles is based on either glycolysis or mitochondrial oxidative phosphorylation (OxPhos). These two bioenergetic pathways are in balanced complementation. Glycolysis is faster than OxPhos, whereas OxPhos is much more efficient. One common feature of both pathways is the compartmentation of high-energy phosphates and their metabolic channeling. The glycolytic muscles are wider, whereas oxidative muscles have significantly more mitochondria. Importantly, a striking difference in bioenergetic mechanisms in oxidative (slow-twitch) versus glycolytic (fast-twitch) muscles and muscle fibers has been clearly shown. The advantage is that the optimal fiber diversity can provide the best muscle function. Various creatine kinase isoforms and phosphocreatine play an important role in glycolytic and oxidative muscles energy metabolism, but their roles are very different, depending on the muscle type. In the glycolytic muscles, phosphocreatine, produced from creatine and ATP by cytosolic creatine kinase, is mostly considered a cellular energy store for fast ATP delivery, whereas in the oxidative muscles, phosphocreatine and mitochondrial creatine kinase are the main players in the intracellular energy transport.

Keywords: Bioenergetics; Cardiac/skeletal muscles energy metabolism; Creatine/phosphocreatine; Intracellular energy transport; Mitochondria; Mitochondrial ROS

DOI: https://doi.org/10.1007/s00424-025-03112-5

J Evol Biol. 2025 Sep 24. pii: voaf111. [Epub ahead of print]

Convergent pathways of reductive mitochondrial evolution characterised with hypercubic inference.

Robert C Glastad, Iain G Johnston.

For a striking example of mitochondrial behaviour beyond ATP generation, consider mitochondrion-related organelles (MROs). Hydrogenosomes, mitosomes, and other reduced mitochondrial forms have evolved through the loss of physical and functional features, from individual electron transport chain (ETC) complexes to oxidative phosphorylaytion and the very ability to produce ATP (and further). Reduction of mitochondria is a dramatic example of convergent evolution, occuring in every eukaryotic kingdom and many parallel times. Here, we use hypercubic inference, a class of methods from evolutionary accumulation modelling (EvAM), to explore the pathways of convergent mitochondrial reduction across eukaryotes. We find that most MRO diversity can be explained by small variations on two distinct pathways, starting with either the loss of Complex I or the loss of Complexes III/IV or TCA cycle steps, which tend to proceed over different characteristic timescales. We show that different clades, including ciliates and apicomplexans, reflect particular instances of these pathways. Using metabolic modelling, we connect the structure of these evolutionary pathways to the metabolic impact of the changes involved, suggesting a plausible explanation for the dramatically convergent nature of reductive evolution. We discuss this approach in connection with related theory on the genetic and functional reduction of mitochondria across organisms.

Keywords: convergent evolution; eukaryotic evolution; metabolism; mitochondria; mitochondrion-related organelles; reductive evolution

DOI: https://doi.org/10.1093/jeb/voaf111

Antioxidants (Basel). 2025 Sep 14. pii: 1115. [Epub ahead of print]14(9):

Integrated Metabolomics and Transcriptomics Reveals Metabolic Pathway Changes in Common Carp Muscle Under Oxidative Stress.

Yongxiang Liu, Bing Li, Yiran Hou, Linjun Zhou, Qiqin Yang, Chengfeng Zhang, Hongwei Li, Jian Zhu, Rui Jia.

Hydrogen peroxide (H2O2), a ubiquitous reactive oxygen species in aquatic ecosystems, has been shown to induce toxicological effects in aquatic animals. However, the molecular mechanisms underlying H2O2-mediated alterations in muscle quality and metabolic homeostasis remain largely unexplored. In this study, we performed integrated metabolomic and transcriptomic analyses to characterize the molecular mechanisms underlying H2O2-induced oxidative stress in fish muscle tissue. Common carp (Cyprinus carpio) were randomized into two groups: a control group (0.0 mM H2O2) and an H2O2-treated group (1.0 mM H2O2) for a 14-day exposure. Following the exposure, comprehensive analyses, including fatty acid composition, amino acid profiles, and multi-omics sequencing, were conducted to elucidate the metabolic responses to oxidative stress. The results showed neither the amino acid nor the fatty acid composition exhibited significant modifications following H2O2 exposure. Metabolomic profiling identified 83 upregulated and 89 downregulated metabolites, predominantly comprising organic acids and derivatives, lipids and lipid-like molecules. These differential metabolites were associated with histidine and purine-derived alkaloid biosynthesis, glyoxylate and dicarboxylate metabolism pathways. Transcriptomic analysis identified 470 upregulated and 451 downregulated differentially expressed genes (DEGs). GO enrichment analysis revealed that these DEGs were significantly enriched in muscle tissue development and transcriptional regulatory activity. KEGG analysis revealed significant enrichment in oxidative phosphorylation, adipocytokine signaling, and PPAR signaling pathways. The elevated oxidative phosphorylation activity and upregulated adipocytokine/PPAR signaling pathways collectively indicate H2O2-induced metabolic dysregulation in carp muscle. Through the integration of metabolomics and transcriptomics, this study offers novel insights into the toxicity of H2O2 in aquatic environments, elucidates adaptive mechanisms of farmed fish to oxidative stress, and provides a theoretical basis for developing antioxidant strategies.

Keywords: Cyprinus carpio; hydrogen peroxide; metabolic functions; multi-omics; nutrient quality; oxidative stress

DOI: https://doi.org/10.3390/antiox14091115

Adv Exp Med Biol. 2025 ;1481 1-28

Molecular Cell Biology of Apoptosis in Health and Disease.

Asma Ahmed, Stephen W G Tait.

Apoptotic cell death is fundamental to the life of multicellular organisms, making central contributions to processes ranging from embryonic development to tissue homeostasis. Two distinct apoptosis pathways have been defined: extrinsic apoptosis and mitochondrial apoptosis. As we discuss, apoptosis is an evolutionary conserved process that is, unsurprisingly, tightly regulated. Inhibition of apoptosis can promote cancer, whereas inappropriate apoptosis has been associated with various neurodegenerative diseases. At its core, apoptosis is initiated and executed by proteases called caspases that, once activated, rapidly dismantle dying cells, ensuring that apoptosis is immunologically silent. In this chapter, we discuss the molecular mechanisms of apoptosis and its evolutionary conservation. Secondly, we highlight the emerging concept that apoptosis signalling can be engaged at non-lethal levels with diverse biological effects. Finally, we provide an overview of how apoptosis can impact health and disease, discussing ways in which apoptosis can be therapeutically targeted.

Keywords: BCL-2 protein family; Caspases; Cell death; Extrinsic apoptosis; MOMP; Mitochondrial apoptosis

DOI: https://doi.org/10.1007/978-3-031-92785-0_1

bioRxiv. 2025 Sep 16. pii: 2025.09.10.675383. [Epub ahead of print]

Beyond Ornithine Metabolism in Gyrate Atrophy: Tissue-Specific Proteomic Insights into Neonatal and Adult OAT Deficiency.

Artjola Puja, Rong Xu, Mark Eminhizer, Tuan Ngo, Ying Zhang, Qingyan Wang, Meghashri Saravanan, Jianhai Du.

Ornithine aminotransferase (OAT) links the urea and TCA cycles by interconverting ornithine to pyrroline-5-carboxylate. Despite its abundance in the liver, OAT mutations primarily cause gyrate atrophy (GA) and blindness. Paradoxically, adult GA patients have hyperornithinemia that is managed by arginine-restricted diet, while neonates experience hypoornithinemia and require arginine supplementation to prevent mortality in animal models. To understand this biochemical paradox, we performed a comprehensive proteomic analysis of the liver, retina, and retinal pigment epithelium and choroid (RPE/Cho) in neonatal and adult Oat rhg mice, a whole-body OAT-deficient model. We found that the number of significantly altered proteins ranged from 5 to 254 across tissues and ages, with minimal changes in the adult retina and greatest changes in the adult RPE/Cho. OAT was the only protein consistently downregulated across all tissues. Neonatal liver proteome was more extensively altered than the adult liver proteome, primarily impacting metabolic pathways, including fatty acid oxidation, detoxification, cholesterol synthesis, and the urea cycle. In contrast, the adult liver showed changes mainly in detoxification and chromosome remodeling. Similarly, the neonatal retina was far more sensitive to OAT deficiency, with alterations not only in metabolism but also in visual transduction, ion and small molecule transport proteins. The RPE/Cho displayed the most pronounced changes in both age groups. In adults, several mitochondrial and signaling proteins were downregulated, while proteins in lipid metabolism, cytoskeleton, and extracellular matrix (ECM) were upregulated. In neonates, the alterations were enriched in chromatin organization, ECM, and vesicle transport. In summary, our findings reveal that OAT is crucial for maintaining age- and tissue-specific proteome homeostasis, with its deficiency leading to alterations in mitochondrial, metabolic processes, and signaling pathways that extend far beyond its canonical role in ornithine metabolism.

DOI: https://doi.org/10.1101/2025.09.10.675383

Nat Commun. 2025 Sep 26. 16(1): 8508

V-ATPase-dependent induction of selective autophagy.

Yuxiang Huang, Dimitra Dialynaki, Yuchen Lei, Zhihai Zhang, Charles R Evans, Daniel J Klionsky.

The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain unclear. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed "V-ATPase-dependent autophagy ". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that V-ATPase-dependent autophagy is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates V-ATPase-dependent autophagy via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide an explanation for the mutational activation of autophagy seen in follicular lymphoma patients.

DOI: https://doi.org/10.1038/s41467-025-63472-5