bims-mionch Biomed News
on Mitochondrial ion channels
Issue of 2024–08–11
seven papers selected by
Gun Kim, Seoul National University
  1. The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases.
  2. Redox Regulation of K+ channel: Role of Thioredoxin.
  3. Potential role of mitochondria and endoplasmic reticulum in the response elicited by D-aspartate in TM4 Sertoli cells.
  4. Implications of endoplasmic reticulum stress and autophagy in aging and cardiovascular diseases.
  5. Targeting mitochondrial damage: shining a new light on immunotherapy.
  6. Organelle communication maintains mitochondrial and endosomal homeostasis during podocyte lipotoxicity.
  7. Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.
  1. Acta Pharmacol Sin. 2024 Aug 08.
    The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases.
    Wen-Bin Zhao, Rui Sheng.
      Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%-20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10-30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.
    Keywords:  Ca2+ homeostasis; cancer; cardiovascular diseases; mitochondria-associated ER membranes; neurodegenerative diseases
    DOI:  https://doi.org/10.1038/s41401-024-01359-9
  2. Antioxid Redox Signal. 2024 Aug 05.
    Redox Regulation of K+ channel: Role of Thioredoxin.
    Robert H Hilgers, Kumuda C Das.
       SIGNIFICANCE: Potassium channels regulate the influx and efflux of K+ ions in various cell types that generate and propagate action potential associated with excitation, contraction and relaxation of various cell types. Although redox active cysteines are critically important for channel activity, redox regulation of K+ channels by thioredoxin has not been systematically reviewed.
    RECENT ADVANCES: Redox regulation of K+ channel is now increasingly recognized as drug targets in pathological condition of several cardiovascular disease processes. The role of thioredoxin in regulation of these channels and its implication in pathological conditions have not been adequately reviewed. This review specifically focuses on the redox-regulatory role of thioredoxin on K+ channel structure and function in physiological and pathophysiological conditions.
    CRITICAL ISSUES: Ion channels including K+ channel have been implicated in the functioning of cardiomyocyte excitation-contraction coupling, vascular hyperpolarization, cellular proliferation, and neuronal stimulation in physiological and pathophysiological conditions. Although, oxidation-reduction of ion channels is critically important in their function, role of thioredoxin, redox regulatory protein in regulation of these channels and its implication in pathological conditions need to be studied to gain further insight into channel function.
    FUTURE DIRECTIONS: Future studies need to map all redox regulatory pathways in channel structure and function using novel mouse models, redox proteomic and signal transduction studies, which modulate various currents and altered excitability of relevant cells implicated in a pathological condition. We are yet at infancy of studies related to redox control of various K+ channels and structured and focused studies with novel animal models.
    DOI:  https://doi.org/10.1089/ars.2023.0416
  3. Front Cell Dev Biol. 2024 ;12 1438231
    Potential role of mitochondria and endoplasmic reticulum in the response elicited by D-aspartate in TM4 Sertoli cells.
    Sara Falvo, Giulia Grillo, Debora Latino, Gabriella Chieffi Baccari, Maria Maddalena Di Fiore, Massimo Venditti, Giuseppe Petito, Alessandra Santillo.
      D-Aspartic Acid (D-Asp) affects spermatogenesis by enhancing the biosynthesis of the sex steroid hormones acting either through the hypothalamus-pituitary-testis axis or directly on Leydig cells. Recently, in vitro studies have also demonstrated the direct effects of D-Asp on the proliferation and/or activity of germ cells. However, although D-Asp is present in Sertoli cells (SC), the specific role of the amino acid in these cells remains unknown. This study investigated the effects of D-Asp on the proliferation and activity of TM4 SC, focusing on the mitochondrial compartment and its association with the endoplasmic reticulum (ER). We found that D-Asp enhanced the proliferation and activity of TM4 cells as evidenced by the activation of ERK/Akt/PCNA pathway and the increase in the protein levels of the androgen receptor. Furthermore, D-Asp reduced both the oxidative stress and apoptotic process. An increase in mitochondrial functionality and dynamics, as well as a reduction in ER stress, were also found in D-Asp-treated TM4 cells. It is known that mitochondria are closely associated with ER to form the Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM), the site of calcium ions and lipid transfer from ER to the mitochondria, and vice versa. The data demonstrated that D-Asp induced stabilization of MAM in TM4 cells. In conclusion, this study is the first to demonstrate a direct effect of D-Asp on SC activity and to clarify the cellular/molecular mechanism underlying these effects, suggesting that D-Asp could stimulate spermatogenesis by improving the efficiency of SC.
    Keywords:  D-aspartate; MAM; Sertoli cells; endoplasmic reticulum stress; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2024.1438231
  4. Front Pharmacol. 2024 ;15 1413853
    Implications of endoplasmic reticulum stress and autophagy in aging and cardiovascular diseases.
    Chenguang Ma, Yang Liu, Zhiling Fu.
      The average lifespan of humans has been increasing, resulting in a rapidly rising percentage of older individuals and high morbidity of aging-associated diseases, especially cardiovascular diseases (CVDs). Diverse intracellular and extracellular factors that interrupt homeostatic functions in the endoplasmic reticulum (ER) induce ER stress. Cells employ a dynamic signaling pathway of unfolded protein response (UPR) to buffer ER stress. Recent studies have demonstrated that ER stress triggers various cellular processes associated with aging and many aging-associated diseases, including CVDs. Autophagy is a conserved process involving lysosomal degradation and recycling of cytoplasmic components, proteins, organelles, and pathogens that invade the cytoplasm. Autophagy is vital for combating the adverse influence of aging on the heart. The present report summarizes recent studies on the mechanism of ER stress and autophagy and their overlap in aging and on CVD pathogenesis in the context of aging. It also discusses possible therapeutic interventions targeting ER stress and autophagy that might delay aging and prevent or treat CVDs.
    Keywords:  ER stress; UPR; aging; autophagy; cardiovascular diseases
    DOI:  https://doi.org/10.3389/fphar.2024.1413853
  5. Front Immunol. 2024 ;15 1432633
    Targeting mitochondrial damage: shining a new light on immunotherapy.
    Wenjuan Zeng, Menghui Wang, Yuxin Zhang, Taicheng Zhou, Zhen Zong.
      Mitochondrial damage has a particular impact on the immune system and tumor microenvironment, which can trigger cell stress, an inflammatory response, and disrupt immune cell function, thus all of which can accelerate the progression of the tumor. Therefore, it is of essence to comprehend how the immune system function and the tumor microenvironment interact with mitochondrial dysfunction for cancer treatment. Preserving the integrity of mitochondria or regulating the function of immune cells, such as macrophages, may enhance the efficacy of cancer therapy. Future research should concentrate on the interactions among mitochondria, the immune system, and the tumor microenvironment to identify new therapeutic strategies.
    Keywords:  immune cells; immunotherapy; mitochondrial damage; target; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1432633
  6. JCI Insight. 2024 Aug 08. pii: e182534. [Epub ahead of print]
    Organelle communication maintains mitochondrial and endosomal homeostasis during podocyte lipotoxicity.
    Sho Hasegawa, Masaomi Nangaku, Yuto Takenaka, Chigusa Kitayama, Qi Li, Madina Saipidin, Yu Ah Hong, Jin Shang, Yusuke Hirabayashi, Naoto Kubota, Takashi Kadowaki, Reiko Inagi.
      Organelle stress exacerbates podocyte injury, contributing to perturbed lipid metabolism. Simultaneous organelle stresses occur in kidney tissues; therefore, a thorough analysis of organelle communication is crucial for understanding the progression of kidney diseases. Although organelles closely interact with one another at membrane contact sites, limited studies have explored their involvement in kidney homeostasis. The endoplasmic reticulum (ER) protein, PDZ domain-containing 8 (PDZD8), is implicated in multiple organelle tethering processes and cellular lipid homeostasis. In this study, we aimed to elucidate the role of organelle communication in podocyte injury using podocyte-specific Pdzd8-knockout mice. Our findings demonstrated that Pdzd8 deletion exacerbated podocyte injury in an accelerated obesity-related kidney disease model. Proteomic analysis of isolated glomeruli revealed that Pdzd8 deletion exacerbated mitochondrial and endosomal dysfunction during podocyte lipotoxicity. Additionally, electron microscopy revealed the accumulation of "fatty abnormal endosomes" in Pdzd8-deficient podocytes during obesity-related kidney diseases. Lipidomic analysis indicated that glucosylceramide accumulated in Pdzd8-deficient podocytes, owing to accelerated production and decelerated degradation. Thus, the organelle-tethering factor, PDZD8, plays a crucial role in maintaining mitochondrial and endosomal homeostasis during podocyte lipotoxicity. Collectively, our findings highlight the importance of organelle communication at the three-way junction among the ER, mitochondria, and endosomes in preserving podocyte homeostasis.
    Keywords:  Chronic kidney disease; Mitochondria; Nephrology; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.182534
  7. Eur J Neurosci. 2024 Aug 05.
    Role of mitochondria-endoplasmic reticulum contacts in neurodegenerative, neurodevelopmental and neuropsychiatric conditions.
    Serangeli Ilaria, Diamanti Tamara, De Jaco Antonella, Miranda Elena.
      Mitochondria-endoplasmic reticulum contacts (MERCs) mediate a close and continuous communication between both organelles that is essential for the transfer of calcium and lipids to mitochondria, necessary for cellular signalling and metabolic pathways. Their structural and molecular characterisation has shown the involvement of many proteins that bridge the membranes of the two organelles and maintain the structural stability and function of these contacts. The crosstalk between the two organelles is fundamental for proper neuronal function and is now recognised as a component of many neurological disorders. In fact, an increasing proportion of MERC proteins take part in the molecular and cellular basis of pathologies affecting the nervous system. Here we review the alterations in MERCs that have been reported for these pathologies, from neurodevelopmental and neuropsychiatric disorders to neurodegenerative diseases. Although mitochondrial abnormalities in these debilitating conditions have been extensively attributed to the high energy demand of neurons, a distinct role for MERCs is emerging as a new field of research. Understanding the molecular details of such alterations may open the way to new paths of therapeutic intervention.
    Keywords:  Alzheimer's disease; ERMCS; MAMs; MERCs; Parkinson's disease; amyotrophic lateral sclerosis; autism spectrum disorders; mood disorders; schizophrenia
    DOI:  https://doi.org/10.1111/ejn.16485
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