bims-smemid 2025-12-07 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2025–12–07
six papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.
Protective effects of α-ketoglutaric acid on palmitic acid-induced deterioration in sheep endometrial epithelial cells via ferroptosis inhibition.
Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.

Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00905-0. [Epub ahead of print]

Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.

Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R Foltz.

  Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.

Keywords:  PRPS; PRPSAP; chromatin; chromatin assembly; histone chaperone; histone deposition; histone supply; metabolism; nucleotide metabolism

DOI:  https://doi.org/10.1016/j.molcel.2025.11.009
Am J Physiol Cell Physiol. 2025 Dec 05.

Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.

Angad Yadav, Susan Schmitt, Wenxia Ma, James A Mobley, Anna Elizabeth Thalacker-Mercer.

  Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration / development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (MyoD1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic mediated control of chromatin state.

Keywords:  Chromatin accessibility; Glutamine metabolism; Succinylation; TCA cycle compartmentalization; myogenesis

DOI:  https://doi.org/10.1152/ajpcell.00568.2025
Nat Metab. 2025 Dec 05.

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

DOI: https://doi.org/10.1038/s42255-025-01410-x
Nat Commun. 2025 Dec 01. 16(1): 10426

Ei24 deficiency in brown adipocytes induces severe hypothermia under cold stress independent of UCP1 activity.

Su Bin Lee, Bui Thanh Thu, Tae Wook Nam, Yaechan Song, Jae Hoon Lee, Yangsik Jeong, Han-Woong Lee.

Brown adipocytes facilitate non-shivering thermogenesis, which is critical for maintaining energy balance and heat production in response to environmental stimuli. Here, we delineate the physiological and biochemical role of etoposide-induced 2.4 (Ei24) in adenosine triphosphate (ATP) production and thermogenesis in brown adipocytes. We generated Ei24 adipocyte-specific knockout (EiaKO) mice that exhibited brown adipose tissue hypertrophy, lipid accumulation, and various mitochondrial abnormalities. Despite mitochondrial defects, uncoupling protein 1 (UCP1) expression and activity remained unchanged. However, those impairments caused lethal hypothermia in mice subjected to cold challenge, underscoring the key role of Ei24 in mitochondrial functions. Mechanistically, Ei24 deficiency disrupted cristae structure, dissipated mitochondrial membrane potential, and reduced matrix pH, leading to severe ATP depletion. We further identify the C-terminal region of Ei24 as essential for supporting ATP synthase function. Those bioenergetic defects not only destabilized the mitochondrial environment necessary for efficient UCP1-mediated thermogenesis, but also impaired ATP-dependent futile cycles such as SERCA-mediated calcium cycling and creatine substrate cycling. Together, our findings indicate that Ei24 functions as a thermogenic regulator that ensures mitochondrial ATP synthesis and structural integrity, enabling both coupled and uncoupled respiration in brown adipose tissue.

DOI: https://doi.org/10.1038/s41467-025-66460-x
Front Vet Sci. 2025 ;12 1617348

Protective effects of α-ketoglutaric acid on palmitic acid-induced deterioration in sheep endometrial epithelial cells via ferroptosis inhibition.

Ziyi Bai, Qinyuan Fang, Shubin Li, Mengxuan Jia, Rongrong Zhang, Chunyu Wang, Zhenli Wu, Gang Liu, Yongbin Liu.

   Introduction: Emerging evidence indicates that dysregulated palmitic acid (PA) homeostasis plays a key role in inducing lipotoxicity and cellular dysfunction in mammalian endometrial epithelial cells. While this phenomenon has been documented in bovine models, the underlying mechanisms of PA-induced toxicity in sheep endometrial epithelial cells (SEECs) remain poorly understood. Moreover, effective strategies to counteract PA-mediated damage in SEECs have yet to be fully explored.
Methods: In this study, we investigated the protective effects of α-ketoglutaric acid (α-KG), a central metabolic intermediate in the tricarboxylic acid (TCA) cycle, against PA-induced cellular impairment in SEECs. Functional assays were performed to assess changes in cell viability, proliferation, migration, lipid accumulation, cell cycle progression, DNA damage, histone trimethylation, and apoptosis. Integrated transcriptomic and metabolomic analyses were conducted to elucidate the molecular pathways involved.
Results and discussion: Our results demonstrated that α-KG markedly alleviated PA-induced cytotoxicity. Specifically, α-KG enhanced cell viability, restored proliferative and migratory capacities, promoted cell cycle progression, and attenuated lipid accumulation, DNA damage, histone trimethylation alteration, and apoptosis. Multi-omics profiling, supported by ferroptosis-specific assays, revealed that these cytoprotective effects were predominantly mediated through the suppression of PA-induced ferroptosis. Collectively, our findings provide novel mechanistic insight into the role of α-KG in mitigating lipid-induced cellular stress and establish its therapeutic potential as a metabolic modulator. This study not only advances our understanding of ferroptosis in reproductive cell biology but also opens new avenues for targeted interventions against lipotoxic damage in endometrial tissues.

Keywords:  ferroptosis; histone trimethylation; palmitic acid; sheep endometrial epithelial cells; α-ketoglutaric acid

DOI:  https://doi.org/10.3389/fvets.2025.1617348
Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.

Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.

  The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor

DOI:  https://doi.org/10.1016/j.cell.2025.11.002