Examinando por Autor "Castro-Sepúlveda, Mauricio"

Mostrando 1 - 6 de 6
  • Miniatura
    Ítem
    The fasting-feeding metabolic transition regulates mitochondrial dynamics
    (Federation of American Society of Experimental Biology (FASEB), 2021-10-10) Castro-Sepúlveda, Mauricio
    In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.
  • Miniatura
    Ítem
    Low abundance of Mfn2 protein correlates with reduced mitochondria-SR juxtaposition and mitochondrial cristae density in human men skeletal muscle: Examining organelle measurements from TEM images
    (Wiley Open Access, 2021-03-08) Castro-Sepúlveda, Mauricio
    The role of mitofusin 2 (Mfn2) in the regulation of skeletal muscle (SM) mitochondria-sarcoplasmic (SR) juxtaposition, mitochondrial morphology, mitochondrial cristae density (MCD), and SM quality has not been studied in humans. In in vitro studies, whether Mfn2 increases or decreases mitochondria-SR juxtaposition remains controversial. Transmission electron microscopy (TEM) images are commonly used to measure the organelle juxtaposition, but the measurements are performed "by-hand," thus potentially leading to between-rater differences. The purposes of this study were to: (1) examine the repeatability and reproducibility of mitochondrial-SR juxtaposition measurement from TEM images of human SM between three raters with different experience and (2) compare the mitochondrial-SR juxtaposition, mitochondrial morphology, MCD (stereological-method), and SM quality (cross-sectional area [CSA] and the maximum voluntary contraction [MVC]) between subjects with high abundance (Mfn2-HA; n = 6) and low abundance (Mfn2-LA; n = 6) of Mfn2 protein. The mitochondria-SR juxtaposition had moderate repeatability and reproducibility, with the most experienced raters showing the best values. There were no differences between Mfn2-HA and Mfn2-LA groups in mitochondrial size, distance from mitochondria to SR, CSA, or MVC. Nevertheless, the Mfn2-LA group showed lower mitochondria-SR interaction, MCD, and VO2max . In conclusion, mitochondrial-SR juxtaposition measurement depends on the experience of the rater, and Mfn2 protein seems to play a role in the metabolic control of human men SM, by regulating the mitochondria-SR interaction.
  • Miniatura
    Ítem
    Mitochondria across the globe: dive rse voices, shared energy
    (Elsevier, 2026-06) Castro-Sepúlveda, Mauricio
    Like mitochondria themselves, research on this organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted Mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages, published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology and Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
  • Miniatura
    Ítem
    Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism
    (Elsevier, 2023-07-01) Castro-Sepúlveda, Mauricio
    Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidation in human skeletal muscle. Evidence shows that an increase in mitochondria-SR interaction and mitochondrial fusion are associated with elevated fatty acid oxidation. In contrast, a decrease in mitochondria-SR interaction and an increase in mitochondrial fission are associated with an elevated glycolytic activity. Based on the evidence reviewed, we postulate two hypotheses for the link between mitochondrial dynamics and insulin resistance in human skeletal muscle. First, glucose and fatty acid availability modifies mitochondria-SR interaction and mitochondrial fusion/fission to help the cell to adapt substrate oxidation appropriately. Individuals with an impaired response to these substrate challenges will accumulate lipid species and develop insulin resistance in skeletal muscle. Second, a chronically elevated substrate availability (e.g. overfeeding) increases mitochondrial production of reactive oxygen species and induced mitochondrial fission. This decreases fatty acid oxidation, thus leading to the accumulation of lipid species and insulin resistance in skeletal muscle. Altogether, we propose mitochondrial dynamics as a potential target for disturbances associated with low fatty acid oxidation.
  • Miniatura
    Ítem
    Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle
    (Frontiers Media S.A., 2023-06-25) Castro-Sepúlveda, Mauricio
    In skeletal muscle (SkM), a reduced mitochondrial elongate phenotype is associated with several metabolic disorders like type 2 diabetes mellitus (T2DM). However, the mechanisms contributing to this reduction in mitochondrial elongate phenotype in SkM have not been fully elucidated. It has recently been shown in a SkM cell line that toll-like receptor 4 (TLR4) contributes to the regulation of mitochondrial morphology. However, this has not been investigated in human SkM. Here we found that in human SkM biopsies, TLR4 protein correlated negatively with Opa1 (pro-mitochondrial fusion protein). Moreover, the incubation of human myotubes with LPS reduced mitochondrial size and elongation and induced abnormal mitochondrial cristae, which was prevented with the co-incubation of LPS with TAK242. Finally, T2DM myotubes were found to have reduced mitochondrial elongation and mitochondrial cristae density. Mitochondrial morphology, membrane structure, and insulin-stimulated glucose uptake were restored to healthy levels in T2DM myotubes treated with TAK242. In conclusion, mitochondrial morphology and mitochondrial cristae seem to be regulated by the TLR4 pathway in human SkM. Those mitochondrial alterations might potentially contribute to insulin resistance in the SkM of patients with T2DM.
  • Miniatura
    Ítem
    Uncovering the muscle clock–mitochondria axis through exercise
    (CellPress, 2025-12) Castro-Sepúlveda, Mauricio
    Emerging evidence suggests an interplay between the molecular clock and mitochondrial dynamics in skeletal muscle. In this Forum article, we hypothesize that exercise, as a metabolic challenge, provides a powerful physiological model to investigate the clock–mitochondria axis and its regulatory role in muscle function and metabolic health in humans.