Angelo D’Alessandro

@ishahjain.bsky.social sorry! Forgot to tag

RBCs are not passive bystanders in systems metabolism. We had been saying this for years. This time, in collaboration with Isha Jain @gladstoneinst.bsky.social

By the way, the Jain lab is on a roll, with ever more elegant science at each paper. It was a pleasure to collaborate!

Red Blood Cells Soak Up Sugar at High Altitude, Protecting Against Diabetes New study shows red blood cells act as hidden glucose sponges in low-oxygen conditions, explaining why people living at high altitude have lower diabetes rates and pointing toward new treatments.

New study shows red blood cells act as hidden glucose sponges in low-oxygen conditions, explaining why people living at high altitude have lower diabetes rates.

@dalessandrolab.bsky.social
@medschool.umaryland.edu
@cp-cellmetabolism.bsky.social
@arcinstitute.org
@ishahjain.bsky.social

Outside back cover of issue 1 of Lab on a Chip: Five channels of lysing blood cells leading to humanoid silhouettes

On the outside back cover of issue 1 of Lab on a Chip:
Surface acoustic wave hemolysis assay for evaluating stored red blood cells.
#OpenAccess from Angelo D'Alessandro, Xiaoyun Ding et al @dalessandrolab.bsky.social @cuanschutz.bsky.social @colorado.edu
Read now: pubs.rsc.org/en/content/a...

Cracking the Code of Blood - Transfusion Today - October 2025

Cracking the code of blood: How genetics and metabolism are transforming transfusions

🔗 Read the full Transfusion Today article here: https://isbtweb.foleon.com/transfusion-today/transfusion-today-october-2025/cracking-the-code-of-blood

#TransfusionMedicine #ISBT #TransfusionToday

Glyoxalase 1 is a proadipogenic gene Diabetes is one of the most prevalent and widespread diseases, with the majority of cases stemming from prolonged obesity. Obesity occurs through the expansion of adipose tissue in an unhealthy and dy...

www.jbc.org/article/S002...

Terrific to have our paper, led by @tjflemin.bsky.social, featured as a plenary article in @bloodjournal.bsky.social today: ashpublications.org/blood/articl...

The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells - The EMBO Journal Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characte...

link.springer.com/article/10.1...

The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells

Congrats to Sweta and to you, Eric!

As always, it takes a village... So grateful to the many collaborators that made this study happen, and to #NIH #NHLBI for the support

#hematology #RBC #RedBloodCell #Erythrocyte #Hypoxia #Exercise #Physiology @cuanschutz.bsky.social

Similar mechanisms exists in plants: under hypoxia-like conditions (high CO₂/low O₂), NO levels rise and S-nitrosate GAPDH at C152, transiently modulating its activity and redirecting carbon flux like in RBCs! This parallel highlights a conserved NO-relay logic tuning metabolism across kingdoms

Together, the data outline a Band 3–BLVRB–hemoglobin network that links oxygen sensing, redox chemistry, and metabolic adaptation in an anucleate cell.

Mechanistically, BLVRB Cys109 functions as an NO-transfer relay, modulating glycolytic enzymes such as GAPDH through S-nitrosation. This provides a redox-based feedback mechanism that tunes metabolism to oxygen availability.

Population-scale RBC proteome-QTL analyses (13,000 donors) show coordinated variation in SLC4A1 and BLVRB abundance, supporting the presence of a conserved regulatory axis across individuals.

In humanized mice, loss of the Band 3 N-terminus disrupts glycolytic activation, lowers 2,3-BPG production, and impairs exercise tolerance, linking this molecular module to whole-organism physiology.

A key finding is that BLVRB (biliverdin reductase B) binds the Band 3 N-terminus under oxygenated conditions and dissociates under hypoxia, when Band 3–deoxyhemoglobin interactions increase. This reversible switch integrates structural, redox, and metabolic control.

Despite the lack of de novo gene expression, the architecture of the human RBC proteome is oxygen responsive through ultra-structural changes. Using deep proteomics, cross-linking interactomics, structural biochemistry, and mouse models, we map how these changes are organized around Band 3 (SLC4A1).

By flow-sorting ultra-pure RBCs, we quantified 3,775 proteins—a high-confidence, contamination-free reference proteome. The full dataset is publicly available in the Deep Red portal:
🔗 angelo-dalessandro.github.io/deep-red-sup...

Yes, Deep Red is a wink to Dario Argento’s classic 1970s thriller!

Deep Red Blood Cell Proteome Defines the Band 3 N-Terminus Interactome as a Regulator of Hypoxic Adaptation via BLVRB-Dependent S-Nitroso Transfer Red blood cells (RBCs) have long been regarded as passive oxygen carriers, yet growing evidence reveals a complex, dynamic proteome independent of de novo gene expression. Here, we define the erythroc...

Labor of love announcement:

Red blood cells make up 83% of the cells in the human body. Mature RBCs lack nuclei (no gene expression) and organelles, and >90% of their dry weight is hemoglobin. Yet we have lacked a clean, contamination-free map of their proteome.
Until now.

doi.org/10.1101/2025...

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia Reduced levels of the essential metabolite heme are a common feature of acute myeloid leukemia, and consequently, leukemic cells are highly sensitive to inhibition of de novo heme synthesis. Blockade ...

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia: Cell www.cell.com/cell/fulltex...

Kudos to the amazing work by @grkeele.bsky.social at RTI International, Gary Churchill @jacksonlab.bsky.social and Jim Zimring at Canadian Blood Services

STEAP3 variation also mapped to several apolipoproteins (including APOA1, APOC3, APOE), linking RBC iron handling to lipid oxidation and vesiculation pathways, potentially bridging neurodegenerative disease biology to RBC iron metabolism with systemic oxidative stress.

This work also represents, to our knowledge, the first pQTL + PTM-QTL map in an enucleated cell type, showing how genetic differences established during erythropoiesis continue to shape the mature RBC proteome through redox and degradative pathways.

A second locus, Steap3, influenced the oxidation of lipids and proteins, vesiculation-related proteins (including several apolipoproteins), and storage-related hemolysis.
Higher Steap3 activity correlated with greater oxidative stress and lower post-transfusion recovery.

We used humanized mice expressing either canonical human HBB or a C93A variant.
Loss of βCys93 altered glutathione balance, increased oxidative modifications, changed proteolytic signatures, and reduced post-transfusion recovery.
These effects align with predictions from the genetic mapping.

The Hbb locus was particularly influential.
Certain founder strains carry an additional cysteine at β13, while others carry only the conserved β93 cysteine.
Variation at these positions was associated with widespread differences in oxidative PTMs and glutathione-related chemistry.

Four loci accounted for much of this trans-regulation:
• Hbb (β-globin)
• Hba (α-globin)
• Steap3 (ferrireductase involved in iron handling)
• Mon1a (vesicular trafficking / iron recycling)

We identified over 6,000 QTLs, with a predominance of trans-acting effects, opposite to nucleated tissues, where cis-pQTLs tend to dominate.
In RBCs, absence of transcription shifts regulatory influence toward genetic effects that modify redox state and protein turnover.

Unlike most tissues, RBCs cannot synthesize new proteins.
This makes them an informative system in which to study post-translational regulation, proteolysis, and oxidative damage.
We quantified proteins, peptides, and 20+ PTM types in both fresh and stored RBCs (blood bank mimicking conditions).