Effects of mitochondrial fusion and fission regulation on mouse hippocampal primary cultures: relevance to Alzheimer's disease
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Background: Alzheimer's disease is a complex disease that begins long before the first well-known pathophysiological signs appear and requires, among other things, new diagnostic approaches. This is primarily due to the lack of effective treatment due to the lack of understanding of the disease mechanisms and the absence of correct biological models reflecting the cause-and-effect relationships in pathogenesis. One of the dysfunctional changes in AD is the disruption of mitochondrial fission and fusion processes. Methods: In this study, mitochondrial fusion and fission were regulated in primary neuro-astrocytic cultures of mouse hippocampus using mitochondrial fission inhibitor, mitochondrial fusion promoter and exogenous zinc. Changes in mitochondrial and cellular morphology were assessed, as well as lipofuscin levels as an early marker of mitochondrial dysfunction. Primary neuro-astrocytic hippocampal cultures of 5xFAD mice, representing a model of hereditary AD, were used for comparison. Results: Use of the mitochondrial fusion promoter converts the mitochondrial network to a pool of fused mitochondria and results in a drop in neuronal density by day 5 of exposure with a concomitant drop in astrocyte density by days 1 and 5 of exposure, accompanied by a drop in lipofuscin fluorescence intensity in culture. The use of mitochondrial fission inhibitor resulted in the appearance of fused mitochondria and disappearance of the pool of smallest mitochondria. This was accompanied by a decrease in neuronal density and an increase in astrocyte density with a concomitant increase in lipofuscin fluorescence intensity to the level of 5xFAD culture. Exogenous zinc induces mitochondrial fragmentation and at high concentrations leads to compensatory astrogliosis and neurodegeneration, while at low concentrations it decreases lipofuscin fluorescence intensity and affects culture morphology and changes in astrocyte immunoreactivity to GFAP. Conclusions: The study demonstrates that changing the processes of mitochondrial dynamics affects the morphology of adult cell cultures and can lead to processes similar to those observed in 5xFAD transgenic cultures. Keywords: Mitochondria, mitochondrial fusion and fission, 5xFAD, lipofuscin, Alzheimer's disease, primaryhippocampal cultureKeywords:
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Mitochondria are dynamic organelles and maintain their structure through two opposing processes of fusion and fission. In mammals, there are many factors which influence the equilibrium between mitochondrial fusion and fission. It has been known that mitochondrial fusion is controlled by mitochondria-shaping proteins, including the large GTPase mitofusins (Mfn1/2) and optic atrophy protein 1 (OPA1), whereas the protein Fis1 and dynamin-related protein 1 (Drp1) are the key mediators of mitochondrial fission. Recent data revealed the relationship between mitochondrial fusion/fission and Ca2+ signaling. Ca2+ handling is controlled by the change of mitochondrial fission-fusion balance. On the other hand, intra- and near-mitochondrial Ca2+ signals can modify mitochondrial morphology and cellular distribution.
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Abstract Mitochondrial structural dynamics is regulated by the fusion or fission of these organelles. Recently published evidence indicates the vital role of mitochondrial fusion and fission in cellular physiology, including progression of apoptosis. These reports indicate that in addition to intimate link between mitochondrial morphogenesis machineries and regulation of mitochondrial steps in apoptosis, certain proteins vital for the regulation of mitochondrial steps in apoptosis can also regulate mitochondrial fusion and fission in healthy cells. In this article, we focus on the regulation of mitochondrial network dynamics. The emerging evidence indicating that proteins implicated in mitochondrial network dynamics are vital for the mitochondrial steps in apoptosis is presented here, as well. Furthermore, the data demonstrating an unexpected role for the B‐cell lymphoma (Bcl)‐2 family members in the regulation of mitochondrial morphogenesis are also discussed. Key concepts: In healthy cells, mitochondrial cycle between several shapes, their morphology result from the equilibrium between mitochondrial fusion and fission. The unique feature of mitochondrial fusion is the necessity of merging double membrane systems from the two fusing mitochondria. This process is mediated by the outer mitochondrial membrane‐associated mitofusin proteins (Mfn1 and Mfn2), and the inner mitochondrial membrane‐associated Opa1. Regulation of mitochondrial fusion and fission has a significant impact on cell viability and early development. The mitochondrial fragmentation occurs concomitantly with the outer mitochondrial membrane (OMM) permeabilization, a critical step in apoptosis. The cooperation between proteins involved in mitochondrial fusion and fission and Bcl‐2 family proteins during apoptosis suggests that changes in mitochondrial network dynamics contribute to apoptotic signalling. The mechanistic link between the core mitochondrial fusion and fission regulating proteins (e.g. Drp1, Mfn2 and Opa1) and proteins from Bcl‐2 family, suggest that Bcl‐2 family proteins also regulate mitochondrial dynamics in healthy cells.
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Though the mitochondrion was initially identified as a key organelle essentially required for energy production and oxidative metabolism, there is considerable evidence that mitochondria are intimately involved in regulating vital cellular processes, such as programmed cell death, proliferation and autophagy. Discovery of mitochondrial "shaping proteins" (Dynamin-related protein (Drp), mitofusins (Mfn) etc.) has revealed that mitochondria are highly dynamic organelles continually changing morphology by fission and fusion processes. Several human pathologies, including cancer, Parkinson's disease, Alzheimer's disease and cardiovascular diseases, have been linked to abnormalities in proteins that govern mitochondrial fission or fusion respectively. Notably, in the context of the heart, defects in mitochondrial dynamics resulting in too many fused and/or fragmented mitochondria have been associated with impaired cardiac development, autophagy, and contractile dysfunction. Understanding the mechanisms that govern mitochondrial fission/fusion is paramount in developing new treatment strategies for human diseases in which defects in fission or fusion is the primary underlying defect. Here, we provide a comprehensive overview of the cellular targets and molecular signaling pathways that govern mitochondrial dynamics under normal and disease conditions. (Circ J 2014; 78: 803-810).
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Abstract Mitochondrial dynamics, a cellular process describing continuous change of shape and location of mitochondria, has drawn much attention recently due to its involvement in cell injury and human pathologies. Mitochondrial fission and fusion are the major processes that alter mitochondrial morphology. Molecular machineries for mitochondrial fission and fusion include proteins of dynamin family large GTPases that remodel biological membranes. Mutations in these proteins cause hereditary diseases or death in human, indicating that mitochondrial fission and fusion are important cellular processes. Identification of additional factors participating in mitochondrial fission and fusion still continues. Recent studies demonstrate that mitochondrial fission/fusion process is under tight regulation through cellular signalling networks and functional states of mitochondria. This information suggests that cellular cues both extrinsic and intrinsic to mitochondria regulate mitochondrial fission and fusion, indicating an important role of mitochondrial fission and fusion in controlling mitochondrial functionality. Many additional pathologies are associated with aberrant mitochondrial fission and fusion, and defining the form–function relationship of mitochondria will be the key for understanding disease aetiology and therapeutic application. Key Concepts: Mitochondria take a variety of shapes depending on cell types and activities. Fission and fusion of mitochondria are the main processes changing their morphology. Dynamin‐related proteins (DRPs) remodel mitochondrial membranes for fission and fusion. Additional proteins and factors including signal‐induced protein modifications participate in mitochondrial fission and fusion. Mutations in genes in mitochondrial fission and fusion are detrimental to human health. Many diseases such as neurodegeneration, metabolic diseases, ischemia‐reperfusion injury, heart diseases, and aging are directly and indirectly associated with dysregulation of mitochondrial fission and fusion.
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Mitochondria are dynamic cell organelles that constantly undergo fission and fusion events. These dynamical processes, which tightly regulate mitochondrial morphology, are essential for cell physiology. Here we propose an elastocapillary mechanical instability as a mechanism for mitochondrial fission. We experimentally induce mitochondrial fission by rupturing the cell's plasma membrane. We present a stability analysis that successfully explains the observed fission wavelength and the role of mitochondrial morphology in the occurrence of fission events. Our results show that the laws of fluid mechanics can describe mitochondrial morphology and dynamics.
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Mitochondria are dynamic organelles that undergo fusion and fission. These active processes occur continuously and simultaneously and are mediated by nuclear-DNA-encoded proteins that act on mitochondrial membranes. The balance between fusion and fission determines the mitochondrial morphology and adapts it to the metabolic needs of the cells. Therefore, these two processes are crucial to optimize mitochondrial function and its bioenergetics abilities. Defects in mitochondrial proteins involved in fission and fusion due to pathogenic variants in the genes encoding them result in disruption of the equilibrium between fission and fusion, leading to a group of mitochondrial diseases termed disorders of mitochondrial dynamics. In this review, the molecular mechanisms and biological functions of mitochondrial fusion and fission are first discussed. Then, mitochondrial disorders caused by defects in fission and fusion are summarized, including disorders related to MFN2, MSTO1, OPA1, YME1L1, FBXL4, DNM1L, and MFF genes.
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Mitochondria are dynamic and are able to interchange their morphology between elongated interconnected mitochondrial networks and a fragmented disconnected arrangement by the processes of mitochondrial fusion and fission, respectively. Changes in mitochondrial morphology are regulated by the mitochondrial fusion proteins (mitofusins 1 and 2, and optic atrophy 1) and the mitochondrial fission proteins (dynamin-related peptide 1 and mitochondrial fission protein 1) and have been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy, although the majority of studies have been largely confined to non-cardiac cells. Despite the unique arrangement of mitochondria in the adult heart, emerging data suggest that changes in mitochondrial morphology may be relevant to various aspects of cardiovascular biology—these include cardiac development, the response to ischaemia–reperfusion injury, heart failure, diabetes mellitus, and apoptosis. Interestingly, the machinery required for altering mitochondrial shape in terms of the mitochondrial fusion and fission proteins are all present in the adult heart, but their physiological function remains unclear. In this article, we review the current developments in this exciting new field of mitochondrial biology, the implications for cardiovascular physiology, and the potential for discovering novel therapeutic strategies for treating cardiovascular disease.
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