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Cell Metabolism Feb 2023Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we...
Mitochondrial components have been abundantly detected in bone matrix, implying that they are somehow transported extracellularly to regulate osteogenesis. Here, we demonstrate that mitochondria and mitochondrial-derived vesicles (MDVs) are secreted from mature osteoblasts to promote differentiation of osteoprogenitors. We show that osteogenic induction stimulates mitochondrial fragmentation, donut formation, and secretion of mitochondria through CD38/cADPR signaling. Enhancing mitochondrial fission and donut formation through Opa1 knockdown or Fis1 overexpression increases mitochondrial secretion and accelerates osteogenesis. We also show that mitochondrial fusion promoter M1, which induces Opa1 expression, impedes osteogenesis, whereas osteoblast-specific Opa1 deletion increases bone mass. We further demonstrate that secreted mitochondria and MDVs enhance bone regeneration in vivo. Our findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of osteogenesis.
Topics: Osteogenesis; Mitochondria; Osteoblasts; Mitochondrial Dynamics; Cell Differentiation
PubMed: 36754021
DOI: 10.1016/j.cmet.2023.01.003 -
FASEB Journal : Official Publication of... Jun 2021Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides,... (Review)
Review
Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.
Topics: Animals; Homeostasis; Humans; Mitochondria; Mitochondrial Dynamics
PubMed: 34048084
DOI: 10.1096/fj.202100067R -
Molecular Cell Mar 2023Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and... (Review)
Review
Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and ultrastructure of mitochondria were depicted as static. The discovery of morphological transitions during cell death and of conserved genes controlling mitochondrial fusion and fission contributed to establishing the concept that mitochondrial morphology and ultrastructure are dynamically regulated by mitochondria-shaping proteins. These finely tuned, dynamic changes in mitochondrial shape can in turn control mitochondrial function, and their alterations in human diseases suggest that this space can be explored for drug discovery. Here, we review the basic tenets and molecular mechanisms of mitochondrial morphology and ultrastructure, describing how they can coordinately define mitochondrial function.
Topics: Humans; Mitochondrial Dynamics; Mitochondria; Cell Death; Signal Transduction; Mitochondrial Proteins
PubMed: 36889315
DOI: 10.1016/j.molcel.2023.02.012 -
Signal Transduction and Targeted Therapy Sep 2023Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature.... (Review)
Review
Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.
Topics: Humans; Mitochondrial Dynamics; Cardiovascular Diseases; Cell Differentiation; Mitochondria; Mitophagy
PubMed: 37669960
DOI: 10.1038/s41392-023-01547-9 -
Acta Pharmacologica Sinica May 2021Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as... (Review)
Review
Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as 'mitochondrial dynamics'. Dynamin-related protein 1 (Drp1) is known as the major pro-fission protein whose activity is tightly regulated to clear the damaged mitochondria via mitophagy, ensuring a strict control over the intricate process of cellular and organ dynamics in heart. Various posttranslational modifications (PTMs) of Drp1 have been identified including phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation, which implicate a role in the regulation of mitochondrial dynamics. An intact mitochondrial homeostasis is critical for heart to fuel contractile function and cardiomyocyte metabolism, while defects in mitochondrial dynamics constitute an essential part of the pathophysiology underlying various cardiovascular diseases (CVDs). In this review, we summarize current knowledge on the critical role of Drp1 in the pathogenesis of CVDs including endothelial dysfunction, smooth muscle remodeling, cardiac hypertrophy, pulmonary arterial hypertension, myocardial ischemia-reperfusion, and myocardial infarction. We also highlight how the targeting of Drp1 could potentially contribute to CVDs treatments.
Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Dynamins; Enzyme Inhibitors; Humans; Mitochondria; Mitochondrial Dynamics; Protein Processing, Post-Translational; Vascular Remodeling
PubMed: 32913266
DOI: 10.1038/s41401-020-00518-y -
Nature Reviews. Cardiology Nov 2022Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial... (Review)
Review
Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
Topics: Actins; Adenosine Triphosphate; Dynamins; GTP Phosphohydrolases; Humans; Mitochondrial Dynamics
PubMed: 35523864
DOI: 10.1038/s41569-022-00703-y -
International Journal of Biological... 2023Ferroptosis is an iron-driven cell death modality characterized by iron accumulation and excessive lipid peroxidation. Ferroptosis is closely related to mitochondrial... (Review)
Review
Ferroptosis is an iron-driven cell death modality characterized by iron accumulation and excessive lipid peroxidation. Ferroptosis is closely related to mitochondrial function, as indicated by studies showing that mitochondrial dysfunction and damage promote oxidative stress, which in turn induces ferroptosis. Mitochondria play crucial roles in cellular homeostasis, and abnormalities in their morphology and function are closely associated with the development of many diseases. Mitochondria are highly dynamic organelles, and their stability is maintained through a series of regulatory pathways. Mitochondrial homeostasis is dynamically regulated, mainly via key processes such as mitochondrial fission, mitochondrial fusion and mitophagy; however, mitochondrial processes are prone to dysregulation. Mitochondrial fission and fusion and mitophagy are intimately related to ferroptosis. Therefore, investigations into the dynamic regulation of mitochondrial processes during ferroptosis are important to provide a better understanding of the development of disease. In this paper, we systematically summarized changes in ferroptosis, mitochondrial fission and fusion and mitophagy to promote an in-depth understanding of the mechanism underlying ferroptosis and provide a corresponding reference for the treatment of related diseases.
Topics: Ferroptosis; Mitochondrial Dynamics; Mitochondria; Mitophagy; Iron; Reactive Oxygen Species
PubMed: 37324946
DOI: 10.7150/ijbs.83348 -
FEBS Letters Apr 2021In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and... (Review)
Review
In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and fusion, as well as distribution along cytoskeletal tracks, are counterbalancing mechanisms acting in concert to maintain a mitochondrial network tuned to cellular function. Balanced mitochondrial dynamics permits quality control of the network including biogenesis and turnover, and distribution of mitochondrial DNA, and is linked to metabolic status. Cellular and organismal health relies on a delicate balance between fission and fusion, and large rearrangements in the mitochondrial network can be seen in response to cellular insults and disease. Indeed, dysfunction in the major components of the fission and fusion machineries including dynamin-related protein 1 (DRP1), mitofusins 1 and 2 (MFN1, MFN2) and optic atrophy protein 1 (OPA1) and ensuing imbalance of mitochondrial dynamics can lead to neurodegenerative disease. Altered mitochondrial dynamics is also seen in more common diseases. In this review, the machinery involved in mitochondrial dynamics and their dysfunction in disease will be discussed.
Topics: Animals; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neurodegenerative Diseases
PubMed: 33742459
DOI: 10.1002/1873-3468.14077 -
Redox Biology Jun 2022As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular...
As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria. Moreover, limiting mitochondrial recruitment of Mfn2 diminished formation of the PINK1/Mfn2/Parkin complex required for initiation of mitophagy resulting in accumulation of damaged mitochondria and ROS (mtROS). Thus, these studies indicate that phospho-Cav-1 may be an important switch mechanism in cancer cell survival which could lead to novel strategies for complementing cancer therapies.
Topics: Caveolin 1; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Mitophagy; Reactive Oxygen Species
PubMed: 35413643
DOI: 10.1016/j.redox.2022.102304 -
Trends in Pharmacological Sciences Feb 2023The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness... (Review)
Review
The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
Topics: Humans; Drug Design; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 36496299
DOI: 10.1016/j.tips.2022.11.004