bims-imesem 2026-07-05 papers

bims-imesem

Biomed News

on Immunemetabolism

Issue of 2026–07–05
six papers selected by
Akshara Kulkarni , University of Cambridge

Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production.
Mapk-driven remodeling of mitochondrial dynamics in melanoma: implications for metabolic plasticity and response to targeted therapy.
Energy beats: Daily and circadian rhythms in mitochondrial biology.
SARS-CoV-2-host and interactions: the dual roles of E3 ubiquitin ligases and ubiquitin-like modification mechanisms in viral infection.
Single nucleotide variant in coenzyme Q6 reprograms macrophage metabolic remodeling in response to inflammatory signals.
Mitochondrial quality control in human ageing and longevity.

bioRxiv. 2026 Jun 23. pii: 2026.06.18.733147. [Epub ahead of print]

Iron Regulates CD4 T Cell Quiescence by Controlling TGF-β Production.

Amber L Siglin, Zelong Han, Afia Nkansah, WanJun Chen, Cheong-Hee Chang.

Transforming growth factor-β (TGF-β) regulates CD4 T cell quiescence, activation, and regulatory T cell differentiation, but its role in T cell iron metabolism is poorly defined. Here, we investigated whether TGF-β regulates iron homeostasis and how iron overload alters TGF-β responsiveness. During T cell activation, TGF-β enhanced survival but markedly reduced proliferation. These effects were accompanied by decreased CD71 expression and cytosolic iron availability, as well as increased mitochondrial iron accumulation. Genetic deletion of TGFβR1 reversed these changes, demonstrating that TGF-β regulates CD4 T cell iron homeostasis through TGFβR1-dependent signaling. Iron-overloaded CD4 T cells lacking the heme exporter FLVCR1 exhibit hypersensitivity to TGF-β, increased TGF-β secretion, and sustained TGFβR1 expression upon activation. Pharmacologic inhibition of TGFβR1restored proliferation, CD71 expression, and iron levels in FLVCR1-deficient cells. Although TGF-β selectively induced total and mitochondrial ROS levels in FLVCR1-deficient cells, antioxidant treatment or Nox2 inhibition did not rescue this phenotype, suggesting that ROS is associated with, but not sufficient to explain, TGF-β hypersensitivity. Acute FeSO 4 -induced iron overload partially recapitulated the phenotype of FLVCR1-deficient cells, although TGFβR1 expression and TGF-β production differed. Finally, regulatory T cells generated in vitro in the presence of TGF-β displayed reduced iron acquisition, and excess iron impaired FoxP3 induction. Together, this work identifies TGF-β as a context-dependent regulator of CD4 T cell iron homeostasis.

DOI: https://doi.org/10.64898/2026.06.18.733147
Biochem Pharmacol. 2026 Jul 02. pii: S0006-2952(26)00550-2. [Epub ahead of print] 118211

Mapk-driven remodeling of mitochondrial dynamics in melanoma: implications for metabolic plasticity and response to targeted therapy.

L F L Prado-Souza, L A Grabauskas, R Chaguri, C D Cardoso, F Y Urushima, L G R Mangini, V S Ramos, Tiago Rodrigues.

  Melanoma is the most aggressive form of skin cancer due to its high metastatic potential and resistance to therapy. Current treatment strategies include surgical resection for localized disease, as well as targeted therapy with MAPK inhibitors and immunotherapy for advanced stages. However, therapeutic resistance and disease relapse remain major clinical challenges. Activating mutations in components of the mitogen-activated protein kinase (MAPK) pathway, particularly in BRAF and NRAS, are among the most frequent oncogenic events in melanoma, driving tumor initiation and progression through sustained ERK signaling. Mitochondria are dynamic organelles whose morphology is regulated by the balance between fission and fusion. In melanoma cells, MAPK-dependent signaling has been implicated in the regulation of key components of the mitochondrial dynamics machinery, thereby reshaping the mitochondrial network. These structural alterations have functional consequences for cellular metabolism, contributing to metabolic plasticity and enabling tumor cells to switch between glycolytic and oxidative metabolic states in response to environmental stimuli and therapeutic pressures. In this review, we discuss current evidence linking oncogenic MAPK signaling to the control of mitochondrial dynamics in melanoma and examine how these processes contribute to metabolic reprogramming. We further explore how mitochondrial remodeling influences therapeutic response and resistance, particularly in the context of MAPK pathway inhibition. Finally, we highlight mitochondrial dynamics as key regulators of metabolic plasticity and as promising therapeutic targets to improve treatment response in melanoma.

Keywords:  Cancer; Drug resistance; Melanoma; Metabolism; Mitochondria; Targeted therapy

DOI:  https://doi.org/10.1016/j.bcp.2026.118211
Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00081-4. [Epub ahead of print] 102191

Energy beats: Daily and circadian rhythms in mitochondrial biology.

Nadia Ceccato, Milena Damulewicz, Gabriella Margherita Mazzotta.

  Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many processes subject to this temporal regulation, mitochondrial function has emerged as a critical and dynamic target of circadian control. Mitochondria, far from being static organelles, undergo continuous morphological remodeling through cycles of fusion and fission, collectively termed mitochondrial dynamics, that are essential for maintaining metabolic homeostasis, energy production, and cellular quality control. Disruptions in circadian rhythmicity, such as those arising from sleep disturbances or irregular feeding patterns, have been associated with impaired glucose tolerance, insulin resistance, and increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Emerging evidence suggests that the circadian clock and mitochondrial dynamics are engaged in a bidirectional interplay, whereby clock-controlled gene expression shapes mitochondrial morphology and function, while mitochondrial metabolic states in turn feedback to influence circadian timing. This review explores the evolutionary origins of mitochondrial rhythmicity, synthesizes current evidence on how the circadian clock regulates mitochondrial dynamics, and examines the physiological and pathological implications of their interconnection. A particular focus is placed on how disruptions in this circadian-mitochondrial axis may contribute to the development of common diseases, including neurodegenerative disorders, metabolic diseases, and cancer, highlighting novel avenues for chronobiologically informed therapeutic strategies.

Keywords:  Circadian clock; Circadian misalignment; Clock-mitochondria interplay; Mitochondrial rhythmicity

DOI:  https://doi.org/10.1016/j.mito.2026.102191
Front Immunol. 2026 ;17 1796416

SARS-CoV-2-host and interactions: the dual roles of E3 ubiquitin ligases and ubiquitin-like modification mechanisms in viral infection.

Jingyi Fu, Zhizhong Mi, Zhaolong Li.

  Following the global outbreak of the COVID-19 pandemic, the interactions between SARS-CoV-2 and host cells have attracted widespread attention. As crucial intracellular enzymes, E3 ubiquitin ligases are involved in numerous physiological processes, including protein degradation, cell cycle regulation, and immune responses. Recent studies have demonstrated that E3 ubiquitin ligases play a pivotal role in the interplay between SARS-CoV-2 and the host. Through interactions with host E3 enzymes, SARS-CoV-2 regulates key processes such as viral replication, immune evasion, and apoptosis. For instance, viral proteins can bind to E3 enzymes to modulate host immune responses and inhibit interferon production, thereby promoting persistent infection. Conversely, E3 enzymes can also regulate the viral life cycle and host cell survival by mediating targeted protein degradation. This mini-review summarizes the roles of E3 ubiquitin ligases in SARS-CoV-2 infection, introduces E3 ligase-mediated ubiquitin-like modifications, and discusses their underlying mechanisms at the virus-host interface. Furthermore, we highlight future research directions and potential therapeutic strategies. Understanding the functions of E3 ubiquitin ligases not only provides novel insights into the pathogenesis of SARS-CoV-2 but also offers promising targets for the development of antiviral therapeutics.

Keywords:  ACE2; E3 ubiquitin ligases; SARS-CoV-2; spike protein; tmprss2

DOI:  https://doi.org/10.3389/fimmu.2026.1796416
Res Sq. 2026 Jun 22. pii: rs.3.rs-9986029. [Epub ahead of print]

Single nucleotide variant in coenzyme Q6 reprograms macrophage metabolic remodeling in response to inflammatory signals.

Xue Lin, Elizabeth M Todd, Edgar P Anaya, Sharon Celeste Morley.

Macrophage metabolic remodeling sustains inflammatory responses to pathogens. At homeostasis, macrophages rely on oxidative phosphorylation (OXPHOS), but during inflammation, OXPHOS is downregulated and aerobic glycolysis increases. Increased flux through the tricarboxylic acid (TCA) cycle increases the availability of substrates, such as succinate, that promote pro-inflammatory transcription. While metabolic remodeling has been extensively characterized, the mechanisms governing the shift from OXPHOS to glycolysis remain unclear. We recently identified a single nucleotide variant (SNV) in a mitochondrial protein, coenzyme Q6 (COQ6), that accelerates OXPHOS downregulation during infection with the Gram-positive organism Streptococcus pneumoniae . Because the SNV converts an aspartate residue (D) to tyrosine (Y), we denote the variant as COQ6 DY . Here, we now systematically compare the inflammatory responses of macrophages expressing Coq6 DY or Coq6 WT after stimulation with the S. pneumoniae -derived pneumolysin (PLY), or with lipopolysaccaharide (LPS; a toxin derived from Gram-negative bacteria). We found that Coq6 DY reprograms macrophage mitochondrial metabolism by changing the balance between OXPHOS and glycolytic activity and relative TCA metabolite concentrations at homeostasis. Furthermore, responses to PLY varied by host genotype and by concentration of available glucose, whereas responses to LPS were less dependent upon genotype. We therefore identify a non-canonical function of COQ6 in governing mitochondrial metabolism.

DOI: https://doi.org/10.21203/rs.3.rs-9986029/v1
Nat Metab. 2026 Jun 29.

Mitochondrial quality control in human ageing and longevity.

Anna Picca, Luigi Ferrucci.

Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.

DOI: https://doi.org/10.1038/s42255-026-01563-3