Thanks, Esteban! Wonderful collaboration with you and Pep!!! 🫂🫂🫂

Wonderful work, David! The concept that ETC flux—not ATP—licenses cDC1 immunogenicity through /metabolite control of DNA methylation is conceptually beautiful. Congrats to Ignacio, Stefanie and the whole team! Thanks for giving us the chance to learn throught this collaboration!

Led by @ignaciohm.bsky.social #CNIC_CARDIO & @swculek.bsky.social @irbbarcelona.org
Thx to @eballestar.bsky.social & other collaborators & funders: @ageinves.bsky.social @erc.europa.eu @comunidadmadrid.bsky.social @contracancerinv.bsky.social @caixaresearch.bsky.social @worldwidecancer.bsky.social

📌 Take home:
An active mitochondrial ETC keeps cDC1s poised for rapid immunogenic responses by tuning redox & metabolite balance controlling DNA methylation—independently of ATP.

🎯 mitochondria-driven metabolite balance controls DC function.
ETC impaired cDC1s fail to prime T cells and show reduced anti tumor immunity in vaccination and melanoma models.
But AOX rescues this, linking DC mitochondrial metabolism → epigenetics → anti cancer immunity.

🛠️ Restoring electron flow without ATP production (via alternative oxidase, AOX) rescues:
✅ metabolite balance
✅ DNA methylation
✅ cDC1 activation & T cell priming
Proof that ETC flux—not energy—licenses immunogenicity.

💡 Loss of ETC function alters key #metabolites:
• ↓ NAD⁺/NADH
• ↑ 2 hydroxyglutarate
• ↑ succinate
These changes impair α KG–dependent enzymes (incl. TET2), coupling mitochondrial metabolism to the #epigenetic poising of cDC1s.

🧬 Mechanism: ETC impairment skews DNA methylation in cDC1s.
We see hypermethylation at PU.1 and AP 1 binding regions, preventing the rapid induction of immediate early immunogenic genes upon activation.

⚠️ Cause: this is NOT about ATP.
Despite ETC disruption, ATP levels, MMP & ROS remain largely intact. Instead, cDC1 dysfunction emerges from disturbed electron flow, #redox & #metabolite balance.
#Mitochondria as signaling hubs regulating #redox & #metabolites, not just batteries.

🔬 We find that cDC1s, but far less cDC2s, rely on intact ETC/OXPHOS to respond rapidly to immunogenic stimuli.
ETC impairment selectively blunts cDC1 activation, costimulation, migration and T cell priming capacity linked to decreased immunogenic response & anti#tumor immunity.

🤔Do you think that OXPHOS in DCs = tolerance?
In our new @cp-cellmetabolism.bsky.social #cnic_cardio & @irbbarcelona.org, we show that active #mitochondrial ETC primes cDC1s for immunogenicity, not tolerance.
Life (& #immunometabolism) is not simple ⚡️
OPEN: www.cell.com/cell-metabol...
#immunoSky

Thanks, Samarth!

Always a mind-blowing talk from @sancholab.bsky.social
who showed, alongside cool data on macs, that cIII inhibition in cDC1 has functional consequence on anti-tumor immunity > mitochondrial ETC disruption impact on histone demethylase and alter PU.1 pioneer activity. Everything linked !

Thanks! 🫂

A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensin…

#WeekendRead! #InterferonPower! Dunphy @sancholab.bsky.social &co show @cp-immunity.bsky.social that in #macrophages, STING leads to type I #IFNs & ISG15-dependent ISGlatyion of mitochondrial proteins, increasing efferocytosis & driving epigenetic remodeling thus supporting inflammation resolution!

Thanks, Ivan! 🫂

#PhD in #immunometabolism on fatty acid oxidation in #macrophage function.
MSCA-DN: unimedizin-mainz.de/unlimited-ms...
For our DC8 position apply in parallel in 2 sites:
1. unimedizin-mainz.de/unlimited-ms...
2. cnic.es/en/convocato...
(DC8: NOT resident in Spain >12m in last 3 years)
#immunosky

The UNLIMITED consortium consists of the following partners: • University Medical Center of Mainz, Germany (Positions #3, #6, #15) • Carlos III National Cardiovascular Research Centre, Spain (Positions #8) • Technical University of Braunschweig, Germany (Positions #9) • Leiden University Medical Centre, Netherlands (Position #12) • Amsterdam Umc Foundation, Netherlands (Position #2) • University of Milan, Italy (Position #7) • University of Padua, Italy (Positions #4) • The Provost, Fellows, Foundation Scholars & The Other Members of Board, of The College of The Holy & Undivided Trinity, Ireland (Position #11) • National Centre for Scientific Research CNRS, France (Position #1) • University of Cologne, Germany (Position #13) • Luxembourg Institute of Health, Luxembourg (Position #14) • Medical University of Vienna, Austria (Position #10) • Vugene UAB, Lithuania (Position #5) Visit https://www.unimedizin-mainz.de/unlimited-msca/consortium.html for all the information and application. Applications must be done in parallel to local positions of each partner that you choose.

Available Positions and Research Topics The UNLIMITED network offers 15 Doctoral Candidate positions across four themes: (1) development of innovative tools for single-cell and spatial analysis of lipid immunometabolism (Subprojects 1–5); (2) molecular pathways linking lipid metabolism to immune activation and differentiation (Subprojects 6–10); (3) tissue-specific and systemic metabolic regulation of immune function (Subprojects 11–13); (4) discovery of therapeutic targets within lipid metabolism (Subprojects 14–15). Collectively, the UNLIMITED network will unravel the lipid–immune interface to generate mechanistic insights that guide the development of precision immunotherapy. Each researcher will receive interdisciplinary, intersectoral training across academia and industry, integrating advanced technologies with transferable and entrepreneurial skills.

Great opportunity for a #PhD on how lipid #metabolism regulates immune cell function in diseases such as cancer and autoimmunity. Train in immunology, bioIT, & metabolism.

Apply in parallel in:
1. UNLIMITED: www.unimedizin-mainz.de/unlimited-ms...
2. Local partner site that you choose.
#immunosky

Led by @gilliandunphy.bsky.social
Thx to coauthors
Thx #CNIC @ageinves.bsky.social @erc.europa.eu @comunidadmadrid.bsky.social @contracancerinv.bsky.social @worldwidecancer.bsky.social @caixaresearch.bsky.social criscancer.org
Open-access: www.cell.com/immunity/ful... #Immunosky

The take home mechanism: An IFN I→ISG15→ATP↑ & MMP↓ pathway enhances efferocytosis, while OMA1 driven fission & reduced ER–mito Ca²⁺ signaling lead to impaired H3K9 histone acetylation that limits ISG amplification—a built in resolve without overreacting program in macrophages. #immunosky

Physiological balance in infection. In a #vaccinia model, ISG15 or OMA1 deficiency leads to lower viral titers by day 7 (more ISGs), but also shows impaired #apoptotic cell clearance (more tissue damage), illustrating the trade off the axis manages during #resolution. #immunosky

Organellar dialog as a brake. IFN-I driven fission reduces ER–mitochondria contact sites, lowers mitochondrial Ca²⁺, and limits histone H3K9 acetylation → restrains ISG amplification. Pharmacologic blockade of mt Ca²⁺ (Ru360) or TCA entry (UK5099) prevents ISG over induction. #immunosky

Additionally, lower MMP activates OMA1, causing mitochondrial fission (confocal & TEM). Blocking fission (OMA1 KO or Mdivi 1) increases ISG induction, revealing #mitochondrial #fission as a negative regulator of ISGs. #immunosky

Function: #efferocytosis gets a boost. IFN-I increases #apoptotic cell uptake by macrophages. This requires #ISG15; #OMA1 mitochondrial protease is dispensable for this step. ISG15 deficiency shows impaired clearance of #apoptotic cells in vivo in thymic or peritoneal challenges. #Immunosky

#ISG15 is the switch. #IFNAR signaling ISGylates mitochondrial proteins (incl. ATP synthase subunit β) to raise ATP and lower MMP. ISGylation deficient ISG15 (AA) fails to rescue; wild type ISG15 (GG) restores ATP↑ & MMP↓
#immunosky

A distinct metabolic signature of #nucleic acid sensing: Unlike TLR ligands, #cytosolic nucleic acid sensing (#STING/#MAVS) or direct IFN I decreases mitochondrial membrane potential (MMP) without collapsing #OXPHOS. Measured by TMRM/JC 1; OCR remains intact. #immunosky

Excessive #inflammation?
We uncover @cp-immunity.bsky.social that #IFN-I via #ISG15 in macrophages lowers #mitochondrial membrane potential, boosts #efferocytosis, and self limits #ISG amplification: a built in brake that promotes resolution. Open-access: www.cell.com/immunity/ful...
#immunosky

A type I IFN-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages @cp-immunity.bsky.social @sancholab.bsky.social
www.cell.com/immunity/ful...

Don't miss the 2nd Conference of the European ImmunoMetabolism Network - EIMN2026
📅10-12th June 2026
📌Luxembourg

immunometnet.eu

@immunometeurope.bsky.social

linkedin.comevents/2ndconferenc...

7/ 🔬 What researcher @sancholab.bsky.social (CNIC) sees as an advance to improve cardiovascular health, artist and #laCaixaFoundFellows @guillermomora.bsky.social sees as a moving map. 🎨

They explain it to us in this #SnapshotsOfTheMonth. 👇

https://bit.ly/3XMZfOc