共查询到20条相似文献,搜索用时 15 毫秒
1.
Jorge M. A. Oliveira 《Journal of bioenergetics and biomembranes》2010,42(3):227-234
Preferential striatal neurodegeneration is a hallmark of Huntington’s disease (HD) pathogenesis, which has been associated
with mitochondrial dysfunction. Evidence from genetic HD models suggest that mutant huntingtin (mHtt) compromises mitochondrial
bioenergetics and dynamics, preventing efficient calcium handling and ATP generation in neuronal networks. Striatal neurons
receive abundant glutamatergic input from the cortex, forming tripartite synapses with astrocytic partners. These are involved
in bidirectional communication, play neuroprotective roles, and emerging evidence suggests that astrocyte dysfunction supports
non-cell autonomous neurodegeneration. In addition to mHtt effects, inherent mitochondria vulnerability within striatal neurons
and astrocytes may contribute for preferential neurodegeneration in HD. Dysfunctional astrocytic mitochondria in cortico-striatal
tripartite synapses might be particularly relevant in the pathogenesis of juvenile/infantile HD, frequently associated with
seizures and abnormally large mHtt polyglutamine expansions. This review discusses our work, primarily addressing in situ
mitochondrial function in neurons and astrocytes, in the context of related work within the HD-mitochondria field. 相似文献
2.
James W. Simpkins Kun Don Yi Shao-Hua Yang James A. Dykens 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration. 相似文献
3.
Martin LJ 《Journal of bioenergetics and biomembranes》2011,43(6):569-579
Amyotrophic lateral sclerosis (ALS) is the third most common human adult-onset neurodegenerative disease. Some forms of ALS
are inherited, and disease-causing genes have been identified. Nevertheless, the mechanisms of neurodegeneration in ALS are
unresolved. Genetic, biochemical, and morphological analyses of human ALS as well as cell and animal models of ALS reveal
that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render
subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations.
Changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins in ALS. Transgenic
mouse models of ALS reveal possible principles governing the biology of neurodegeneration that implicate mitochondria and
the mitochondrial permeability transition pore. This paper reviews how mitochondrial pathobiology might contribute to the
mechanisms of neurodegeneration in ALS. 相似文献
4.
5.
In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases. 相似文献
6.
Loss of neurons is a hallmark of neurodegenerative disorders and there is increasing evidence suggesting that apoptosis is a key mechanism by which neurons die in these diseases. Mitochondrial dysfunction has been implicated in this process of neuronal cell death, but there is a growing body of evidence suggesting also an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondria, or in concert with mitochondrial-initiated pathways. Investigations in our laboratory have focused on neuronal injury resulting from the administration of aluminum maltolate, via the intracisternal route, to New Zealand white rabbits. This treatment induces both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent aluminum-induced neuronal death by interfering with the mitochondrial and/or the endoplasmic reticulum-mediated apoptosis cascade. Cytochrome c release from mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis cascade; this is prevented by lithium treatment. GDNF also protects against aluminum-induced apoptosis but by upregulation of Bcl-X(L), thereby preventing the binding of cytochrome c to Apaf-1. This animal model system involving neurotoxicity induced by an aluminum compound provides new information on mechanisms of neurodegeneration and neuroprotection. 相似文献
8.
Maria Damiano Laurie Galvan Nicole Déglon Emmanuel Brouillet 《生物化学与生物物理学报:疾病的分子基础》2010,1802(1):52-61
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca2+ buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca2+ homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as “sensors” of the neurochemical environment, play a central role in striatal degeneration in HD. 相似文献
9.
In animal cell, mitochondria are the main sites of the synthesis of ATP required for cell functioning and survival. On the other hand, mitochondria play a key role in initiating cell programmed death (apoptosis). In addition, defects in the mitochondrial genome and in the nuclear genome encoding mitochondrial proteins may result in malfunctioning of these organelles and, as result, in diseases of the whole organism. This article contains basic information on the functioning of oxidative phosphorylation and on mitochondrial production of reactive oxygen species. It also describes initiation of apoptosis at the mitochondrial level. Finally, it briefly presents some most common genetic defects responsible for "mitochondrial diseases". 相似文献
10.
Onyango IG 《Neurochemical research》2008,33(3):589-597
Environmental toxins, genetic predisposition and old age are major risk factors for Parkinson’s disease (PD). Although the
mechanism(s) underlying selective dopaminergic (DA) neurodegeneration remain unclear, molecular studies in both toxin based
models and genetic based models of the disease suggest a major etiologic role for mitochondrial dysfunction in the pathogenesis
of PD. Further, recent studies have presented clear evidence for a high burden of mtDNA deletions within the substantia nigra
neurons in individuals with PD. Ultimately, an understanding of the molecular events which precipitate DA neurodegeneration
in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review recent advances and
current understanding of the genetic factors, molecular mechanisms and animal models of PD. 相似文献
11.
Lysosomal storage diseases (LSDs) are debilitating genetic conditions that frequently manifest as neurodegenerative disorders. They severely affect eye, motor and cognitive functions and, in most cases, abbreviate the lifespan. Postmitotic cells such as neurons and mononuclear phagocytes rich in lysosomes are most often affected by the accumulation of undegraded material. Cell death is well documented in parts of the brain and in other cells of LSD patients and animal models, although little is known about mechanisms by which death pathways are activated in these diseases, and not all cells exhibiting increased storage material are affected by cell death. Lysosomes are essential for maturation and completion of autophagy-initiated protein and organelle degradation. Moreover, accumulation of effete mitochondria has been documented in postmitotic cells whose lysosomal function is suppressed or in aging cells with lipofuscin accumulation. Based upon observations in the literature and our own data showing similar mitochondrial abnormalities in several LSDs, we propose a new model of cell death in LSDs. We suggest that the lysosomal deficiencies in LSDs inhibit autophagic maturation, leading to a condition of autophagic stress. The resulting accumulation of dysfunctional mitochondria showing impaired Ca2+ buffering increases the vulnerability of the cells to pro-apoptotic signals. 相似文献
12.
Recent findings from genetic studies suggest that defective mitochondrial quality control may play an important role in the
development of Parkinson's disease (PD). Such defects may result in the impairment of neuronal mitochondria, which leads to
both synaptic dysfunction and cell death and results in neurodegeneration. Here, we review state-of-the-art knowledge of how
pathways affecting mitochondrial quality control might contribute to PD, with a particular emphasis on the molecular mechanisms
employed by PTEN-induced putative kinase 1 (PINK1), HtrA2 and Parkin to regulate mitochondrial quality control. 相似文献
13.
Proteomic approach to studying parkinson’s disease 总被引:4,自引:0,他引:4
Parkinson’s disease is a common age-related neurodegenerative disease characterized pathologically by a loss of dopaminergic
neurons in the substantia nigra with resultant depletion of striatal dopamine and presence of Lewy bodies in the remaining
neurons. The Lewy body contains numerous functional and structural proteins, including α-synuclein and ubiquitin; aggregation
of α-synuclein is thought to be important in Lewy body formation as well as neurodegeneration, although the detailed mechanisms
remain to be defined. Increasing evidence has suggested that mitochondrial dysfunction, increased oxidative stress, and dysfunction
of the ubiquitin-proteasome system may be involved in α-synuclein aggregation, Lewy body formation, and neurodegeneration.
However, how these processes are related to each other is not fully understood, given that there are Parkinsonian animal models
as well as human diseases with significant nigral neurodegeneration regardless of whether Lewy bodies form or not. This review
summarizes the current related research fields and proposes a proteomic approach to investigate the mechanisms that may dictate
α-synuclein aggregation, Lewy body formation, and neurodegeneration. 相似文献
14.
Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia 总被引:14,自引:0,他引:14
Schapira AH 《Biochimica et biophysica acta》1999,1410(2):159-170
Respiratory chain dysfunction has been identified in several neurodegenerative disorders. In Friedreich's ataxia (FA) and Huntington's disease (HD), where the respective mutations are in nuclear genes encoding non-respiratory chain mitochondrial proteins, the defects in oxidative phosphorylation are clearly secondary. In Parkinson's disease (PD) the situation is less clear, with some evidence for a primary role of mitochondrial DNA in at least a proportion of patients. The pattern of the respiratory chain defect may provide some clue to its cause; in PD there appears to be a selective complex I deficiency; in HD and FA the deficiencies are most severe in complex II/III with a less severe defect in complex IV. Aconitase activity in HD and FA is severely decreased in brain and muscle, respectively, but appears to be normal in PD brain. Free radical generation is thought to be of importance in both HD and FA, via excitotoxicity in HD and abnormal iron handling in FA. The oxidative damage observed in PD may be secondary to the mitochondrial defect. Whatever the cause(s) and sequence of events, respiratory chain deficiencies appear to play an important role in the pathogenesis of neurodegeneration. The mitochondrial abnormalities induced may converge on the function of the mitochondrion in apoptosis. This mode of cell death is thought to play an important role in neurodegenerative diseases and it is tempting to speculate that the observed mitochondrial defects in PD, HD and FA result directly in apoptotic cell death, or in the lowering of a cell's threshold to undergo apoptosis. Clarifying the role of mitochondria in pathogenesis may provide opportunities for the development of treatments designed to reverse or prevent neurodegeneration. 相似文献
15.
So Jung Park Ji Hyun Shin Jae In Jeong Ji Hoon Song Yoon Kyung Jo Eun Sung Kim Eunjoo H. Lee Jung Jin Hwang Eun Kyung Lee Sun Ju Chung Jae-Young Koh Dong-Gyu Jo Dong-Hyung Cho 《The Journal of biological chemistry》2014,289(4):2195-2204
Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRNA library and identified mortalin as a potential regulatory protein. Both genetic and chemical inhibition of mortalin strongly induced mitochondrial fragmentation and synergistically increased Aβ-mediated cytotoxicity as well as mitochondrial dysfunction. Importantly we determined that the expression of mortalin in Alzheimer disease (AD) patients and in the triple transgenic-AD mouse model was considerably decreased. In contrast, overexpression of mortalin significantly suppressed Aβ-mediated mitochondrial fragmentation and cell death. Taken together, our results suggest that down-regulation of mortalin may potentiate Aβ-mediated mitochondrial fragmentation and dysfunction in AD. 相似文献
16.
Jennings JJ Zhu JH Rbaibi Y Luo X Chu CT Kiselyov K 《The Journal of biological chemistry》2006,281(51):39041-39050
Mucolipidosis type IV is a genetic lysosomal storage disease associated with degenerative processes in the brain, eye, and other tissues. Mucolipidosis type IV results from mutations in the gene MCOLN1, which codes for the TRP family ion channel, mucolipin 1. The connection between lysosomal dysfunction and degenerative processes in mucolipidosis type IV is unclear. Here we report that mucolipidosis type IV and several unrelated lysosomal storage diseases are associated with significant mitochondrial fragmentation and decreased mitochondrial Ca2+ buffering efficiency. The mitochondrial alterations observed in these lysosomal storage diseases are reproduced in control cells by treatment with lysosomal inhibitors and with the autophagy inhibitor 3-methyladenine. This suggests that inefficient autophagolysosomal recycling of mitochondria generates fragmented, effete mitochondria in mucolipidosis. Mitochondria accumulate that cannot properly buffer calcium fluxes in the cell. A decrease in mitochondrial Ca2+ buffering capacity in cells affected by these lysosomal storage diseases is associated with increased sensitivity to apoptosis induced by Ca2+-mobilizing agonists and executed via a caspase-8-dependent pathway. Deficient Ca2+ homeostasis may represent a common mechanism of degenerative cell death in several lysosomal storage diseases. 相似文献
17.
By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established. 相似文献
18.
Parkinson's disease: mechanisms and models 总被引:54,自引:0,他引:54
Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process. 相似文献
19.
Carsten Merkwirth Paola Martinelli Anne Korwitz Michela Morbin Hella S. Br?nneke Sabine D. Jordan Elena I. Rugarli Thomas Langer 《PLoS genetics》2012,8(11)
Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics. 相似文献
20.
《Autophagy》2013,9(7):1144-1145
A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration. 相似文献