Biology subjects

Marti-Mateos, Y.

Publications and source records attributed to Marti-Mateos, Y..

6 recordsLinked to original sources

bioRxiv2026

Branched-chain amino acid fermentation as an alternative mammalian electron sink

Hypoxia disrupts mitochondrial respiration and increases the NADH/NAD+ ratio, causing reductive stress. To maintain redox homeostasis, mammalian cells divert electrons toward fermentation. While fermentation in mammals typically involves lactate production, we identify the fermentation of branched-chain amino acids (BCAAs) as an alternative electron sink activated by hypoxia. The resulting metabolites are excreted in urine as a distinct mechanism for alleviating reductive stress. BCAA fermentation is catalyzed by lactate dehydrogenase (LDH) enzymes and is highly responsive to the NADH/NAD+ ratio. Consequently, BCAA fermentation products are sensitive biomarkers for reductive stress in human contexts ranging from resistance exercise to severe hypoxemia. Furthermore, we find that mouse sperm have evolved highly efficient BCAA fermentation, providing a specific metabolic strategy to support the anaerobic electron flow that facilitates flagellar hypermotility across mammalian sperm. Our work highlights an under-appreciated fate of BCAAs in response to reductive stress.

cell biology↗

bioRxiv2026

Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia

Cardiac function depends on continuous oxidative metabolism, rendering cardiomyocytes highly vulnerable to oxygen deprivation. Here, we performed a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived cardiomyocytes to identify genes that modulate survival during chronic hypoxia. This screen revealed that knockdown of basigin (BSG), a chaperone for the monocarboxylate transporters MCT1 and MCT4, confers robust protection. Canonically, hypoxic cells suppress pyruvate dehydrogenase (PDH) activity to reduce the oxidation of major fuel sources, thereby limiting TCA cycle flux, lowering oxygen consumption, and minimizing reactive oxygen species generated by an overly reduced electron transport chain (ETC). In contrast, we found that BSG inhibition reverses this response, prioritizing ATP maintenance during hypoxia and enhancing cardiomyocyte survival. Mechanistically, BSG loss restricts lactate efflux, leading to decreased PDH phosphorylation and increased glucose uptake for oxidation. Consistent with this, ETC subunits are more essential under hypoxia, highlighting cardiomyocytes unusual reliance on aerobic ATP production even when oxygen is limited. These findings challenge prevailing models of hypoxic adaptation by revealing cardiomyocyte-specific bioenergetic requirements and motivating future therapeutic efforts.

cell biology↗

bioRxiv2025

MIF-induced CD74+ microglia/macrophages are clinically relevant disease-associated subpopulations in brain metastasis and other CNS disorders

The upregulation of CD74, a chaperone involved in MHC-II antigen processing 1,2, has been broadly reported in virtually all brain disorders analyzed by single-cell RNA sequencing 3-6. However, its expression is usually interpreted as indicative of antigen presentation. In parallel, CD74 expression has also been described in cancer cells across multiple tumor types, but interestingly in glioma its expression has been mainly identified in the microenvironment. However, the functional contribution of CD74 to disease progression in the brain, and specifically in secondary brain tumors, has not been directly addressed. Here we described that, in contrast to what it has been assumed, the presence of CD74+ microglia/macrophages, which is induced by increased levels of interferon gamma in the brain affected by metastases, does not relate to its canonical pathway. Instead, CD74s alternative function as cytokine receptor is pivotal. Rewired by increasing levels of its ligand MIF, produced by proliferating cancer cells, the CD74 receptor, upon binding to this ligand, translocates to the nucleus activating a NF-{kappa}B-dependent program promoting metastasis progression. A brain metastasis-associated CD74 signature involves a more aggressive progression of the local disease in patients, while it has no clinical correlation with the matched primary tumor. Furthermore, we identified the CD74+ myeloid population in additional brain disorders including Alzheimers disease and multiple sclerosis, which shared a pan-disease non-canonical signature with clinical relevance. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreases brain metastases in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. Our findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a novel vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders, guided by a non-invasive molecular strategy.

cancer biology↗

bioRxiv2025

Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude

High altitude conditions result in improved glucose tolerance and lower diabetes risk across species, yet the underlying physiological mechanism remains unclear. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance, independent of insulin sensitivity. This effect persisted for weeks after mice returned to normoxia. PET-CT imaging revealed that internal organs explained only a small fraction of increased glucose uptake in hypoxia, suggesting the presence of an unknown glucose sink. We hypothesized that increased glucose tolerance might be linked to the hypoxia-induced increase in red blood cells (RBCs), whose metabolism relies entirely on glucose. Experimental manipulation of RBC numbers through phlebotomy or transfusion directly altered blood glucose levels, demonstrating the necessity and sufficiency of RBCs as primary glucose sinks in hypoxia. Moreover, RBCs produced during systemic hypoxia exhibited a sustained [~]3-fold increase in glucose uptake, rapidly synthesizing the hemoglobin allosteric regulator 2,3-DPG that allows for increased oxygen release in hypoxia. Therapeutically, we demonstrated that both chronic hypoxia and our recently developed pharmacological hypoxia mimetic, HypoxyStat, effectively rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as critical regulators of systemic glucose metabolism under hypoxic conditions, illuminating a conserved physiological adaptation and suggesting novel therapeutic avenues for hyperglycemic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/650365v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@b6e505org.highwire.dtl.DTLVardef@175e720org.highwire.dtl.DTLVardef@198efdborg.highwire.dtl.DTLVardef@1ab2418_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Na+/H+ antiporter activity by respiratory complex I controls mitochondrial membrane potential and is impaired in LHON disease

The mitochondrial electron transport chain (mETC) converts the energy of substrate oxidation into a H+ electrochemical gradient ({Delta}p), which is composed by an inner mitochondrial membrane (IMM) potential ({Delta}{Psi}mt) and a pH gradient ({Delta}pH). So far, {Delta}{Psi}mt has been assumed to be composed exclusively by H+. Mitochondrial Ca2+ and Na+ homeostasis, which are essential for cellular function, are controlled by exchangers and antiporters in the inner mitochondrial membrane (IMM). In the last few years, some of them have been identified, except for the Na+-specific mitochondrial Na+/H+ exchanger (mNHE). Here, using a rainbow of mitochondrial and nuclear genetic models, we have identified the P-module of complex I (CI) as the major mNHE. In turn, its activity creates a Na+ gradient across the IMM, parallel to {Delta}pH, which accounts for half of the {Delta}{Psi}mt in coupled respiring mitochondria. We have also found that a deregulation of this mNHE function in CI, without affecting its enzymatic activity, occurs in Leber hereditary optic neuropathy (LHON), which has profound consequences in {Delta}{Psi}mt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

biochemistry↗

bioRxiv2019

Functional role of respiratory supercomplexes in mice: segmentation of the Qpool and SCAF1

Mitochondrial respiratory complexes assemble into different forms of supercomplexes (SC). In particular, SC III2+IV require the SCAF1 protein. However, the structural role of this factor in the formation of the respirasome (I+III2+IV) and the physiological role of SCs are controversial. Here, we study C57BL/6J mice harbouring either non-functional SCAF1, the full knock-out for SCAF1 or the wild-type version of the protein and found a growth and exercise phenotype due to the lack of functional SCAF1. By combining quantitative data-independent proteomics, high resolution 2D Blue Native Gel Electrophoresis and functional analysis of enriched respirasome fractions, we show that SCAF1 confers structural attachment between III2 and IV within the respirasome, increases NADH-dependent respiration and reduces ROS production. Furthermore, through the expression of AOX in cells and mice we confirm that CI-CIII superassembly segments the CoQ in two pools and modulates CI-NADH oxidative capacity. These data demonstrate that SC assembly, regulated by SCAF1, modulates the functionality of the electron transport chain.

molecular biology↗