Biology subjects

Montero, M.

Publications and source records attributed to Montero, M..

3 recordsLinked to original sources

bioRxiv2026

High-throughput screen identifies a potent MCU activator boosting cardiac contractile bioenergetics

Mitochondrial Ca2+ uptake through the mitochondrial calcium uniporter complex (MCUc) couples intracellular Ca2+ signaling to energy metabolism and cellular function. Despite its physiological importance, potent and selective pharmacological activators of the MCU complex remain scarce, and existing compounds show modest specificity. Here, we screened 1,280 bioactive compounds and identified CGP7930 as a potent activator of mitochondrial Ca2+ uptake. Mechanistically, the compound required MICU1, but not MICU2, to exert its effects. Molecular docking, non-covalent interaction analysis, and site-directed mutagenesis identified Gln304 and Val307 in MICU1 as critical determinants of compound activity. In addition to directly stimulating MCU activity, CGP7930 increased mitochondria-endoplasmic reticulum contact sites, suggesting an additional mechanism to facilitate inter-organellar Ca2+ transfer. CGP7930 promoted Ca2+-dependent activation of mitochondrial energy metabolism in cardiomyocytes and boosted the contractile performance of the mice hearts. This effect was MCU-dependent, as hearts from MCU KO mice failed to increase the ventricular contraction force upon CGP7930 perfusion. Molecular docking, non-covalent interaction analysis, and site-directed mutagenesis identified Gln304 and Val307 in MICU1 as critical determinants of compound activity.

biochemistry↗

bioRxiv2026

Multi-echo BOLD fMRI improves cerebrovascular reactivity estimates in stroke

Cerebrovascular reactivity (CVR), the ability of cerebral blood vessels to dilate or constrict in response to a vasoactive stimulus, is a clinically meaningful measure of cerebrovascular health. Head motion and other noise sources substantially impact CVR quality, particularly in clinical populations. In this study, we evaluated multi-echo fMRI techniques, including optimal combination of echoes (ME-OC) and multi-echo independent component analysis (ME-ICA), for improving CVR quality relative to single-echo fMRI in participants with stroke. In a breath-hold fMRI dataset, ME-OC significantly improved CVR quality metrics and reduced the percentage of negative CVR values in normal-appearing gray and white matter (p<0.05). ME-ICA reduced the dependence of BOLD signals on head motion but did not improve CVR quality metrics. In a separate resting-state dataset, ME-OC effects were largely consistent with the breath-hold dataset, but ME-ICA also significantly improved CVR quality metrics and reduced negative CVR values in normal-appearing gray and white matter relative to ME-OC (p<0.05). These findings demonstrate that multi-echo fMRI can improve CVR estimation in clinical populations, particularly in low signal-to-noise datasets, enhancing the feasibility of CVR analyses in stroke studies and allowing for better visualization of stroke-related CVR deficits.

neuroscience↗

bioRxiv2025

Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans

Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis. HighlightsO_LIgsr-1a or trxr-2 single mutants have no overt phenotypes. C_LIO_LIgsr-1a trxr-2 double mutants are viable but show small size, gonad migration defects and reduced progeny. C_LIO_LILoss of both reductases in mitochondria triggers a constitutive ATFS-1-dependent UPRmt. C_LIO_LIATFS-1 is essential for gsr-1a trxr-2 worms survival. C_LIO_LIgsr-1a trxr-2 animals remodel mitochondrial morphology in a tissue-specific manner. C_LIO_LIgsr-1a trxr-2 double mutants exhibit impaired muscle and sperm function but enhanced wound healing. C_LI Graphical abstract (to be incorporated)

genetics↗