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Cell Reports Aug 2023Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and...
Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.
Topics: GTP Phosphohydrolases; Phosphoric Monoester Hydrolases; Phosphoglycerate Mutase; Mitochondrial Dynamics; Mitochondrial Proteins; Dynamins
PubMed: 37498743
DOI: 10.1016/j.celrep.2023.112895 -
Tumour Biology : the Journal of the... May 2017Cancer is among the leading causes of death worldwide, and the number of new cases continues to rise. Despite recent advances in diagnosis and therapeutic strategies,... (Review)
Review
Cancer is among the leading causes of death worldwide, and the number of new cases continues to rise. Despite recent advances in diagnosis and therapeutic strategies, millions of cancer-related deaths occur, indicating the need for better therapies and diagnostic strategies. Mitochondria and metabolic alterations have been recognized as important for cancer progression. However, a more precise understanding of how to manipulate mitochondria-related processes for cancer therapy remains to be established. Mitochondria are highly dynamic organelles which continually fuse and divide in response to diverse stimuli. Participation in the aforementioned processes requires a precise regulation at many levels that allows the cell to couple mitochondrial activity to nutrient availability, biosynthetic demands, proliferation rates, and external stimuli. The many functions of these organelles are intimately linked to their morphology. Recent evidence suggests an important link between mitochondrial morphology and disease, including neurodegenerative, inflammatory diseases and cancer. Here, we review recent advances in the understanding of mitochondrial dynamics with a special focus on its relationship to tumor progression.
Topics: Humans; Mitochondria; Mitochondrial Dynamics; Neoplasms
PubMed: 28468591
DOI: 10.1177/1010428317698391 -
Current Opinion in Genetics &... Jun 2016Mitochondria are highly abundant in and essential to the beat-to-beat contractile performance of hearts. However, relatively few cardiac diseases have been attributed to... (Review)
Review
Mitochondria are highly abundant in and essential to the beat-to-beat contractile performance of hearts. However, relatively few cardiac diseases have been attributed to primary mitochondrial dysfunction. The paucity of evidence for 'primary mitochondrial cardiac diseases' may be because such an entity does not exist. Alternately, the consequences of mitochondrial dysfunction on hearts may be so severe that long-term viability is severely impaired and affected individuals are therefore not included in standard genetic screens of adult heart disease subjects. Here, I review accumulating experimental evidence that impairing mitochondrial fission or fusion causes cardiomyopathy in otherwise normal mice, and consider how these data could motivate screening of perinatal cardiomyopathy subjects for damaging mutations of mitochondrial fission and fusion factors.
Topics: Animals; Cardiomyopathies; Humans; Mice; Mitochondria; Mitochondrial Dynamics; Myocytes, Cardiac
PubMed: 27061490
DOI: 10.1016/j.gde.2016.03.001 -
Nutrients May 2023The bone synthesizing function of osteoblasts (OBs) is a highly demanding energy process that requires nutrients. However, how nutrient availability affects OBs behavior...
BACKGROUND
The bone synthesizing function of osteoblasts (OBs) is a highly demanding energy process that requires nutrients. However, how nutrient availability affects OBs behavior and bone mineralization remain to be fully understood.
METHODS
MC3T3-E1 cell line and primary OBs (OBs) cultures were treated with physiological levels of glucose (G; 5.5 mM) alone or with the addition of palmitic acid (G+PA) at different concentrations. Mitochondria morphology and activity were evaluated by fluorescence microscopy, qPCR, and oxygen consumption rate (OCR) measurement, and OBs function was assessed by mineralization assay.
RESULTS
The addition of non-lipotoxic levels of 25 μM PA to G increased mineralization in OBs. G+25 μM PA exposure reduced mitochondria size in OBs, which was associated with increased activation of dynamin-related protein 1, a mitochondrial fission protein, enhanced mitochondria OCR and ATP production, and increased expression of oxidative phosphorylation genes. Treatment with Mdivi-1, a putative inhibitor of mitochondrial fission, reduced osteogenesis and mitochondrial respiration in OBs.
CONCLUSIONS
Our results revealed that OBs function was enhanced in the presence of glucose and PA at 25 μM. This was associated with increased OBs mitochondrial respiration and dynamics. These results suggest a role for nutrient availability in bone physiology and pathophysiology.
Topics: Mitochondrial Dynamics; Glucose; Mitochondrial Proteins; Nutrients; Osteoblasts
PubMed: 37432387
DOI: 10.3390/nu15092222 -
International Journal of Molecular... Jan 2022Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in... (Review)
Review
Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion-fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.
Topics: Animals; Cardiovascular System; Estradiol; Female; Gene Expression Regulation; Humans; Male; Mitochondria; Mitochondrial Dynamics; Nervous System; Receptors, Estrogen; Sex Characteristics
PubMed: 35163044
DOI: 10.3390/ijms23031118 -
Antioxidants & Redox Signaling May 2022Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged... (Review)
Review
Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged mitochondria is a hallmark of cardiac diseases. Disruption of quality control systems that maintain mitochondrial number, size, and shape through fission/fusion balance and mitophagy results in dysfunctional mitochondria, defective mitochondrial segregation, impaired cardiac bioenergetics, and excessive oxidative stress. Pharmacological tools that improve the cardiac pool of healthy mitochondria through inhibition of excessive mitochondrial fission, boosting mitochondrial fusion, or increasing the clearance of damaged mitochondria have emerged as promising approaches to improve the prognosis of heart diseases. There is a reasonable amount of preclinical evidence supporting the effectiveness of molecules targeting mitochondrial fission and fusion to treat cardiac diseases. The current and future challenges are turning these lead molecules into treatments. Clinical studies focusing on acute (., myocardial infarction) and chronic (., heart failure) cardiac diseases are needed to validate the effectiveness of such strategies in improving mitochondrial morphology, metabolism, and cardiac function. 36, 844-863.
Topics: Heart Failure; Humans; Mitochondria; Mitochondrial Dynamics; Mitophagy; Myocardial Infarction
PubMed: 35044229
DOI: 10.1089/ars.2021.0145 -
Scientific Reports Dec 2022Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries, characterized by the death of retinal pigment epithelial...
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries, characterized by the death of retinal pigment epithelial (RPE) cells and photoreceptors. Previous studies report an accumulation of damaged and dysfunctional mitochondria in RPE of human donors with AMD. Understanding how damaged mitochondria accumulate in AMD is an important step in discovering disease mechanisms and identifying therapeutic targets. In this report, we assessed mitochondrial fission and fusion by quantifying proteins and measured mitochondrial autophagy (mitophagy) via protein analysis and advanced imaging techniques using mitochondrial targeted mKeima in primary human RPE from donors with or without AMD. We report disease-specific differences in mitochondrial proteins that regulate fission, fusion, and mitophagy that were present at baseline and with treatments to stimulate these pathways. Data suggest AMD RPE utilize receptor-mediated mitophagy as a compensatory mechanism for deficits in the ubiquitin-mediated mitophagy pathway. These changes in mitochondrial homeostasis could lead to the buildup of damaged and dysfunctional mitochondria observed in the RPE of AMD donors.
Topics: Humans; Retinal Pigment Epithelium; Mitochondrial Dynamics; Oxidative Stress; Macular Degeneration; Autophagy
PubMed: 36526679
DOI: 10.1038/s41598-022-26012-5 -
International Journal of Molecular... Apr 2021Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the... (Review)
Review
Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.
Topics: Animals; Humans; Immunity, Cellular; Immunity, Innate; Mitochondria; Mitochondrial Dynamics
PubMed: 33923929
DOI: 10.3390/ijms22084260 -
Nature Communications Mar 2022Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving...
Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.
Topics: Animals; Cytoskeletal Proteins; Drosophila; Dynamins; GTP-Binding Proteins; Mammals; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Peptide Elongation Factors
PubMed: 35332133
DOI: 10.1038/s41467-022-29071-4 -
Handbook of Experimental Pharmacology 2017Mitochondria are an essential component of multicellular life - from primitive organisms, to highly complex entities like mammals. The importance of mitochondria is... (Review)
Review
Mitochondria are an essential component of multicellular life - from primitive organisms, to highly complex entities like mammals. The importance of mitochondria is underlined by their plethora of well-characterized essential functions such as energy production through oxidative phosphorylation (OX-PHOS), calcium and reactive oxygen species (ROS) signaling, and regulation of apoptosis. In addition, novel roles and attributes of mitochondria are coming into focus through the recent years of mitochondrial research. In particular, over the past decade the study of mitochondrial shape and dynamics has achieved special significance, as they are found to impact mitochondrial function. Recent advances indicate that mitochondrial function and dynamics are inter-connected, and maintain the balance between health and disease at a cellular and an organismal level. For example, excessive mitochondrial division (fission) is associated with functional defects, and is implicated in multiple human diseases from neurodegenerative diseases to cancer. In this chapter we examine the recent literature on the mitochondrial dynamics-function relationship, and explore how it impacts on the development and progression of human diseases. We will also highlight the implications of therapeutic manipulation of mitochondrial dynamics in treating various human pathologies.
Topics: Animals; Disease Models, Animal; Dynamins; GTP Phosphohydrolases; Humans; Mice; Microtubule-Associated Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neurodegenerative Diseases
PubMed: 28040850
DOI: 10.1007/164_2016_38