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Mitochondria are essential organelles in eukaryotic cells that control such diverse processes as energy metabolism, calcium buffering, and cell death. Recent studies have revealed that changes in mitochondrial morphology by fission and fusion, a process known as mitochondrial dynamics, is particularly important for neuronal function and survival. Defects in this process are commonly found in neurodegenerative diseases, offering a new paradigm for investigating mechanisms of neurodegeneration. To provide researchers working on neurodegenerative diseases and mitochondria with updated information on this rapidly progressing field, we have invited experts in the field to critically review recent progresses and identify future research directions. The topics include genetics of mitochondrial dynamics, mitochondrial dynamics and bioenergetics, autophagy, apoptosis, and axonal transport, and its role in neurological diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Mitochondria are essential organelles in eukaryotic cells that control such diverse processes as energy metabolism, calcium buffering, and cell death. Recent studies have revealed that changes in mitochondrial morphology by fission and fusion, a process known as mitochondrial dynamics, is particularly important for neuronal function and survival. Defects in this process are commonly found in neurodegenerative diseases, offering a new paradigm for investigating mechanisms of neurodegeneration. To provide researchers working on neurodegenerative diseases and mitochondria with updated information on this rapidly progressing field, we have invited experts in the field to critically review recent progresses and identify future research directions. The topics include genetics of mitochondrial dynamics, mitochondrial dynamics and bioenergetics, autophagy, apoptosis, and axonal transport, and its role in neurological diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Abstract : Mitochondria are dynamic, double-membraned organelles responsible for many processes within the cell, including ATP production, calcium buffering, and the stress response. Mitochondria are highly networked throughout the cell and can change shape and size to respond to the energy and stress demands of the cell. These changes are governed by the processes of mitochondrial fission and fusion. Disruptions in mitochondrial dynamics play a role in a variety of diseases, including neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD). How these deficits contribute to cellular pathology, however, is still largely unknown. In this work, we investigated the role of mitochondrial morphology and function in stress resistance and neurodegeneration in the nematode C. elegans. We found, using in vivo imaging of the mitochondria, that mitochondrial networks fragment in response to different stresses. Furthermore, mutations in mitochondrial fission and fusion genes alter stress resistance. We also found that in models of PD, dysfunctional mitochondria accumulate with age, and disruption of the mitochondrial unfolded protein response decreases lifespan and worsens phenotypes in these worms. Finally, we also found disrupted mitochondrial networks in worm models of HD and uncover novel mitochondrial targets in HD models that increase lifespan and improve physiologic rates. This work demonstrates the importance of mitochondrial dynamics and function in stress resistance and neurodegenerative disease and identifies novel targets for neurodegenerative disease focusing on mitochondrial dysfunction.
This dissertation, "Characterization of Mitochondrial Morphology and Dynamics in Neurodegeneration" by Hiu-ling, Hung, 洪曉翎, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Mitochondria are ubiquitous organelles which are crucial for life and death pathways in the cell, including ATP production, Ca2+ homeostasis, and regulation of apoptosis. Dynamics of mitochondrial network (fission, fusion, and transport) are important for maintaining proper functions of the organelle. Mitochondria continuously undergo fission and fusion to regulate their morphology, distribution, turnover, and transportation within the cell. Heterogeneity of mitochondrial morphology has been described within and between cells. Furthermore, increasing lines of evidence have shown distinct shapes of mitochondria in response to different stress stimuli. Recently, abnormal mitochondrial dynamics have been implicated in various neurodegenerative diseases. Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting over 36 millions of people worldwide. In AD, patients suffer from gradual deteriorations in cognitive abilities, which eventually lead to death. With over a hundred years of research, the underlying mechanisms of this incurable disease remain obscure. In the current study, the role of mitochondrial dynamics in AD was investigated. During apoptosis, tubular mitochondrial network breaks into punctate spheres in which the process is often referred as mitochondrial fragmentation. While mitochondrial fragmentation is an important pathological event at later stages of neurodegeneration, the role of mitochondrial dynamics at early stages of disease progression is not well understood. Moreover, the relationship between mitochondrial morphology and functions remains obscure. Furthermore, it is unclear if mitochondrial fragmentation is a straightforward process in the course of neurodegeneration. In this study, the temporal effects of I-Amyloid (A-) on mitochondrial morphology and functions were investigated. At early time points following AAAtreatments, mitochondria rapidly transformed from tubular to granular morphology. The induction of granular mitochondria was shown to be associated with increase in mitochondrial oxidative stress induced by A Using simultaneous photoactivation and fluorescence recovery after photobleaching (SPA-FRAP), mitochondrial dynamics were found to be impaired by Am-induced oxidative stress. Despite the drastic changes in morphology, mitochondrial functions remained intact. Thus, changes in organelle morphology do not necessarily accompany impairment in organelle functions. Furthermore, the induction of granular mitochondria could be abolished by inhibition of fission, suggesting that it might be a transient process. Granular mitochondria were defined as a novel phenotype of mitochondria, which is morphologically and functionally distinct from mitochondrial fragmentation in apoptosis. With prolonged Anntreatment, mitochondria exhibited a variety of distinct morphologies, including short and elongated tubules, granular-, and circular-shaped. Particularly, a subset of neurons exhibited extensively elongated mitochondria. Hyperfusion of mitochondrial network was proposed to be a protective mechanism against Aa-induced cellular stress. It is evident that mitochondria undergo dynamic changes in morphology during neurodegeneration. Taken together, an adaptation model of mitochondrial dynamics in neurodegeneration was proposed. It was speculated that granular mitochondria are triggered as an initial response to increased oxidative stress. Wi
Mitochondrial dysfunction is an early event in many neurodegenerative diseases, with impaired bioenergetics and migration acting as neurodegenerative triggers. Mitochondrial disruption in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress is observed in several disease models. Mitochondria are essential for cellular function due to their role in ATP production, metabolic regulation, cell cycling, signaling pathways, and development. Neurons are responsible for buffering calcium fluxes during synaptic transmission while providing the energy for vesicle release and recycling, maintenance of membrane potential, and axonal and dendritic transport. Maintaining healthy mitochondria is crucial to meet the bioenergetic demands of a neuron and is achieved by maintaining a careful balance between mitochondrial biogenesis, transport, dynamics and mitophagy. In glaucoma, increased intraocular pressure is a stressor for ganglion cells and is implicated in dysfunction of the mitochondrial fusion proteins, Mitofusin 1 and Mitofusin 2, that regulate mitochondrial dynamics and transport. Here we propose that post-translational modifications of mitofusins disrupt mitochondria dynamics and transport. We found impaired mitochondrial dynamics and transport result in the accumulation of Mitofusin 2 in the somas of the retinal ganglion cells, intervening in the dissemination of energy throughout the axons, resulting in the eventual death of the neurons. Based on our findings, we propose a mechanism by which mitochondrial dysfunction is triggered in glaucoma via intraocular pressure through the inactivation of kinases.
Mitochondria play important roles in neuronal function and survival, including ATP production, Ca2 buffering, and apoptosis. Mitochondrial dysfunction is a common event in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD); however, what causes the mitochondrial dysfunction remains unclear. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1) and fusion by mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1), which are essential for mitochondrial function. Mutations in the mitochondrial fission and fusion machinery lead to neurodegeneration. Thus, whether defective mitochondrial dynamics participates in ALS and HD requires further investigation. ALS is a fatal neurodegenerative disease characterized by upper and lower motor neuron loss. Mutations in Cu/Zn superoxide dismutase (SOD1) cause the most common familiar form of ALS by mechanisms not fully understood. Here, a new motor neuron-astrocyte co-culture system was created and live-cell imaging was used to evaluate mitochondrial dynamics. Excessive mitochondrial fission was observed in mutant SOD1[superscript G]93[superscript A] motor neurons, correlating with impaired axonal transport and neuronal cell death. Inhibition of mitochondrial fission restored mitochondrial dynamics and protected neurons against SOD1[superscript G]93[superscript A]-induced mitochondrial fragmentation and neuronal cell death, implicating defects in mitochondrial dynamics in ALS pathogenesis. HD is an inherited neurodegenerative disorder caused by glutamine (Q) expansion in the polyQ region of the huntingtin (HTT) protein. In the current work, mutant HTT caused mitochondrial fragmentation in a polyQ-dependent manner in both primary cortical neurons and fibroblasts from human patients. An abnormal interaction between DRP1 and HTT was observed in mutant HTT mice and inhibition of mitochondrial fission or promotion of mitochondrial fusion restored mitochondrial dynamics and protected neurons against mutant HTT-induced cell death. Thus, mutant HTT may increase mitochondrial fission by elevating DRP1 GTPase activity, suggesting that mitochondrial dynamics plays a causal role in HD. In summary, rebalanced mitochondrial fission and fusion rescues neuronal cell death in ALS and HD, suggesting that mitochondrial dynamics could be the molecular mechanism underlying these diseases. Furthermore, DRP1 might be a therapeutic target to delay or prevent neurodegeneration.
This second edition brings together up-to-date contributions from leaders in the field internationally on the various ways in which mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. The reader is guided through the basic functions of mitochondria and the mechanisms that lead to their dysfunction, and on to the consequences of this dysfunction for neuronal function before finishing with the modelling of these disorders and discussion of new potential therapeutic targets. Additional chapters have been added to the book to reflect advances in the field and there are many new contributors and topics, including how mitochondria are degraded and the interaction of the mitochondria with pathologically relevant proteins. Mitochondrial Dysfunction in Neurodegenerative Disorders provides an accessible, authoritative guide to this important area for neurologists; research and clinical neuroscientists; neuropathologists; and residents with an interest in clinical research.
Biopsies and post-mortem tissue of patients with multiple sclerosis (MS) as well as inflammatory demyelinating animal models show that endoplasmic reticulum (ER) stress is a hallmark of the progression of these pathologies. Moreover, MS biopsies and animal models of neuroinflammatory diseases have detected axonal damage associated with mitochondria fragmentation and impaired distribution as an early event in absence of demyelination. It is thought that a combination of these phenomena makes cells more susceptible to inflammatory--mediated neurodegeneration and subsequent progression of the disease. Recent studies have demonstrated that Rab32, a small GTPase in the Ras protein family, plays a role in regulating mitochondrial mobility and ER stress induced apoptosis. Liang et al. showed that Rab32 expression sharply increases in response to acute brain inflammation, but subsequently drops. Based on the finding that activation of Rab32 induces ER stress related apoptosis and facilitates mitochondrial fragmentation via activation of dynamin-related protein 1 (Drp1), we hypothesize that Rab32 could play a role in altering the axonal mitochondrial distribution and inducing neurodegeneration in MS. In this study, we probed and measured the levels of Rab32 protein and functional related proteins Rab38 and Rab7L1, ER stress and apoptosis related proteins in acute as well as chronic lesions and normal-appearing white matter (NAWM) of inflamed MS brain tissues by Western blot and immunohistochemistry. Indeed, we found that high levels of Rab32 coincide with ER stress-associated apoptosis in acute lesions and its activation leads to shorter neurites with fragmented mitochondria in human neurons. Moreover, abnormal expression and activity of Rab32 accelerates apoptosis of human neurons, suggesting a role for Rab32 in neurodegenerative progression of MS.