Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo
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Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.Keywords:
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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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Abstract The dynamicity of the mitochondrial network is crucial for meeting the ever‐changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well‐organized in young, healthy C. elegans , but become fragmented and disorganized with advancing age and in models of age‐associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp‐1 or the mitochondrial fusion genes fzo‐1 and eat‐3 , individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
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Mitochondria are frequently described as the powerhouse of the cell for apparent reasons. However, these organelles are dynamic was not known until recently. Scientists have found that mitochondria must undergo well-organized cycles of fragmentation/fission and fusion to maintain structural integrity, size, and distribution. These fission and fusion events are collectively called “mitochondrial dynamics” and are considered crucial for regulating organelle function. Mitochondrial fission accounts for the division of one mitochondrion into two. It is regulated by GTPase dynamin-related protein 1 (DRP1) and its adaptor proteins such as mitochondrial fission protein 1 (FIS1), mitochondrial fission factor (MFF), and mitochondrial dynamics protein of 49 and 51 kDa (Mid49, Mid51). DRP1, a cytosolic protein, is recruited to mitochondria to cause fragmentation upon activation through upregulation of serine 616 and downregulation of serine 637 phosphorylation. In contrast, mitochondrial fusion involves the fusion of two separate small mitochondria into one large mitochondrion, thereby generating a network of elongated or tubular mitochondria. These fusion events are regulated by GTPase dynamin-like proteins located on the outer (Mitofusin 1, MFN1 and mitofusin 2, MFN2) and inner (optic atrophy protein 1, OPA1) mitochondrial membrane. Fission is generally coupled with apoptosis, while fusion is associated with pro-survival signals. However, cancer cells can utilize mitochondrial dynamics, depending on their cellular state; this is reflected in the current conflicting literature explaining mitochondrial fission or fusion influencing tumor progression. Nonetheless, alterations in mitochondrial dynamics have been implicated as one of the key factors in tumor progression and therapeutic resistance across a wide spectrum of cancers. As a result, targeting mitochondrial dynamics is emerging as a potential strategy for solid tumors.
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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 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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Mitochondria are dynamic organelles that change morphology by controlled fission and fusion events. Mitochondrial fission is regulated by a conserved protein complex assembled at the outer membrane. Human MTP18 is a novel nuclear-encoded mitochondrial membrane protein, implicated in controlling mitochondrial fission. Upon overexpression of MTP18, mitochondrial morphology was altered from filamentous to punctate structures suggesting excessive mitochondrial fission. Mitochondrial fragmentation was blocked in cells coexpressing either the mitochondrial fusion protein Mfn1 or Drp1K38A, a dominant negative version of the fission protein Drp1. Also, a loss-of function of endogenous MTP18 by RNA interference (RNAi) resulted in highly fused mitochondria. Moreover, MTP18 appears to be required for mitochondrial fission because it is blocked after overexpression of hFis1 in cells with RNAi-mediated MTP18 knockdown. In conclusion, we propose that MTP18 functions as an essential intramitochondrial component of the mitochondrial division apparatus, contributing to the maintenance of mitochondrial morphology.
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