Andrew B Knott | University of Central Florida (original) (raw)
Papers by Andrew B Knott
Annals of the New York Academy of Sciences, 2008
Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, ... more Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, the cause of this dysfunction remains a mystery. Here, we discuss the potential role of mitochondrial fission and fusion in the onset and progression of neurodegenerative diseases. Specifically, we propose that an imbalance in mitochondrial fission and fusion may underlie both familial and sporadic neurodegenerative disorders. There is substantial evidence that links disruption of the mitochondrial fission and fusion equilibrium, resulting in abnormally long or short mitochondria, to neurodegeneration. First, hereditary mutations in the mitochondrial fusion GTPases optic atrophy-1 and mitofusin-2 cause neuropathies in humans. In addition, recent findings report increased mitochondrial fission in Parkinson's disease (PD) models and induction of mitochondrial fission by two proteins, PTEN-induced kinase 1 and parkin, which are mutant in familial forms of PD. Furthermore, mutant huntingtin, the disease-causing protein in Huntington's disease, alters mitochondrial morphology and dynamics. Rotenone, a pesticide and inducer of PD symptoms, and amyloid-beta peptide, which is causally linked to Alzheimer's disease, initiate mitochondrial fission. Finally, mitochondrial fission is an early event in ischemic stroke and diabetic neuropathies. In sum, a growing body of research suggests that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments and cures for neurodegenerative diseases.
Trends in Neurosciences, 2008
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that g... more Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills and normal movements. Although research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key part in HD pathogenesis. Here, we highlight how mutant huntingtin (mtHtt) might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, mitochondrial membrane potential and Ca(2+) buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which, in turn, might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria might dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.
Methods, 2008
Mitochondrial morphology and length change during fission and fusion and mitochondrial movement v... more Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microscopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.
Nature Reviews Neuroscience, 2008
Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochond... more Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA (mtDNA) mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in mitochondrial fusion GTPases (mitofusin-2 and optic atrophy-1), neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired TOC Blurb: There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Here, Bossy-Wetzel and colleagues discuss how aberrant mitochondrial fission and fusion can contribute to neurodegenerative disease.
Antioxidants & Redox Signaling, 2009
Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a... more Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration. Antioxid. Redox Signal. 11, 541-553.
Journal of Alzheimer's disease : JAD, 2010
Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer'... more Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer's disease (AD) and might play a causative role in disease onset and progression. The underlying mechanisms of mitochondrial and synaptic dysfunction in AD remain unclear. We previously reported that nitric oxide (NO) triggers persistent mitochondrial fission and causes neuronal cell death. A recent article claimed that S-nitrosylation of dynamin related protein 1 (DRP1) at cysteine 644 causes protein dimerization and increased GTPase activity and is the mechanism responsible for NO-induced mitochondrial fission and neuronal injury in AD, but not in Parkinson's disease (PD). However, this report remains controversial. To resolve the controversy, we investigated the effects of S-nitrosylation on DRP1 structure and function. Contrary to the previous report, S-nitrosylation of DRP1 does not increase GTPase activity or cause dimerization. In fact, DRP1 does not exist as a dimer under nat...
Diabetes, Obesity and Metabolism, 2010
Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also c... more Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also converts into toxic radical species that can damage cells through a process known as nitrosative stress. While the physiological roles of NO in blood vessel dilation, the nervous system and the immune system are well established, recent studies have begun to investigate the role of NO in metabolism and energy expenditure through modulation of mitochondria. NO appears to stimulate mitochondrial biogenesis in certain situations through activation of proteins such as peroxisome proliferator-activated receptor γ (PPARγ ) co-activator 1α (PGC1-α). Because of this link between NO and mitochondrial biogenesis, the role of NO in certain aspects of metabolism, including exercise response, obesity, fat cell differentiation and caloric restriction, are the subject of increasing investigation. In addition to its role in mitochondrial biogenesis, NO also stimulates mitochondrial fragmentation, which can be caused by too much mitochondrial fission or inhibition of mitochondrial fusion and can result in bioenergetic failure. While the contribution of NO-mediated mitochondrial fragmentation to neurodegenerative diseases seems clear, the mechanisms by which NO causes fragmentation are uncertain and controversial. In this review, we discuss the role of NO in manipulation of mitochondrial biogenesis and dynamics and how these events contribute to human health-and age-related disease.
Cell Death and Differentiation, 2007
Diabetes, obesity & metabolism, 2010
Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also c... more Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also converts into toxic radical species that can damage cells through a process known as nitrosative stress. While the physiological roles of NO in blood vessel dilation, the nervous system and the immune system are well established, recent studies have begun to investigate the role of NO in metabolism and energy expenditure through modulation of mitochondria. NO appears to stimulate mitochondrial biogenesis in certain situations through activation of proteins such as peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC1-α). Because of this link between NO and mitochondrial biogenesis, the role of NO in certain aspects of metabolism, including exercise response, obesity, fat cell differentiation and caloric restriction, are the subject of increasing investigation. In addition to its role in mitochondrial biogenesis, NO also stimulates mitochondrial fragmentation, which can be caused by too much mitochondrial fission or inhibition of mitochondrial fusion and can result in bioenergetic failure. While the contribution of NO-mediated mitochondrial fragmentation to neurodegenerative diseases seems clear, the mechanisms by which NO causes fragmentation are uncertain and controversial. In this review, we discuss the role of NO in manipulation of mitochondrial biogenesis and dynamics and how these events contribute to human health- and age-related disease.
Antioxidants & Redox Signaling, 2009
Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a... more Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration. Antioxid. Redox Signal. 11, 541-553.
Annals of the New York Academy of Sciences, 2008
Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, ... more Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, the cause of this dysfunction remains a mystery. Here, we discuss the potential role of mitochondrial fission and fusion in the onset and progression of neurodegenerative diseases. Specifically, we propose that an imbalance in mitochondrial fission and fusion may underlie both familial and sporadic neurodegenerative disorders. There is substantial evidence that links disruption of the mitochondrial fission and fusion equilibrium, resulting in abnormally long or short mitochondria, to neurodegeneration. First, hereditary mutations in the mitochondrial fusion GTPases optic atrophy-1 and mitofusin-2 cause neuropathies in humans. In addition, recent findings report increased mitochondrial fission in Parkinson's disease (PD) models and induction of mitochondrial fission by two proteins, PTEN-induced kinase 1 and parkin, which are mutant in familial forms of PD. Furthermore, mutant huntingtin, the disease-causing protein in Huntington's disease, alters mitochondrial morphology and dynamics. Rotenone, a pesticide and inducer of PD symptoms, and amyloid-β peptide, which is causally linked to Alzheimer's disease, initiate mitochondrial fission. Finally, mitochondrial fission is an early event in ischemic stroke and diabetic neuropathies. In sum, a growing body of research suggests that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments and cures for neurodegenerative diseases.
Methods, 2008
Mitochondrial morphology and length change during fission and fusion and mitochondrial movement v... more Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microcopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.
Trends in Neurosciences, 2008
Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that gradually robs aff... more Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills, and normal movements. While research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key role in HD pathogenesis. Here, we highlight how mtHtt might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, membrane potential and Ca 2+ buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which in turn might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria may dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.
Nature Reviews Neuroscience, 2008
Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochond... more Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA (mtDNA) mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in mitochondrial fusion GTPases (mitofusin-2 and optic atrophy-1), neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired TOC Blurb: There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Here, Bossy-Wetzel and colleagues discuss how aberrant mitochondrial fission and fusion can contribute to neurodegenerative disease.
Cell death and differentiation, 2007
Annals of the New York Academy of Sciences, 2008
Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, ... more Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, the cause of this dysfunction remains a mystery. Here, we discuss the potential role of mitochondrial fission and fusion in the onset and progression of neurodegenerative diseases. Specifically, we propose that an imbalance in mitochondrial fission and fusion may underlie both familial and sporadic neurodegenerative disorders. There is substantial evidence that links disruption of the mitochondrial fission and fusion equilibrium, resulting in abnormally long or short mitochondria, to neurodegeneration. First, hereditary mutations in the mitochondrial fusion GTPases optic atrophy-1 and mitofusin-2 cause neuropathies in humans. In addition, recent findings report increased mitochondrial fission in Parkinson's disease (PD) models and induction of mitochondrial fission by two proteins, PTEN-induced kinase 1 and parkin, which are mutant in familial forms of PD. Furthermore, mutant huntingtin, the disease-causing protein in Huntington's disease, alters mitochondrial morphology and dynamics. Rotenone, a pesticide and inducer of PD symptoms, and amyloid-beta peptide, which is causally linked to Alzheimer's disease, initiate mitochondrial fission. Finally, mitochondrial fission is an early event in ischemic stroke and diabetic neuropathies. In sum, a growing body of research suggests that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments and cures for neurodegenerative diseases.
Trends in Neurosciences, 2008
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that g... more Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills and normal movements. Although research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key part in HD pathogenesis. Here, we highlight how mutant huntingtin (mtHtt) might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, mitochondrial membrane potential and Ca(2+) buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which, in turn, might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria might dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.
Methods, 2008
Mitochondrial morphology and length change during fission and fusion and mitochondrial movement v... more Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microscopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.
Nature Reviews Neuroscience, 2008
Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochond... more Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA (mtDNA) mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in mitochondrial fusion GTPases (mitofusin-2 and optic atrophy-1), neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired TOC Blurb: There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Here, Bossy-Wetzel and colleagues discuss how aberrant mitochondrial fission and fusion can contribute to neurodegenerative disease.
Antioxidants & Redox Signaling, 2009
Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a... more Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration. Antioxid. Redox Signal. 11, 541-553.
Journal of Alzheimer's disease : JAD, 2010
Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer'... more Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer's disease (AD) and might play a causative role in disease onset and progression. The underlying mechanisms of mitochondrial and synaptic dysfunction in AD remain unclear. We previously reported that nitric oxide (NO) triggers persistent mitochondrial fission and causes neuronal cell death. A recent article claimed that S-nitrosylation of dynamin related protein 1 (DRP1) at cysteine 644 causes protein dimerization and increased GTPase activity and is the mechanism responsible for NO-induced mitochondrial fission and neuronal injury in AD, but not in Parkinson's disease (PD). However, this report remains controversial. To resolve the controversy, we investigated the effects of S-nitrosylation on DRP1 structure and function. Contrary to the previous report, S-nitrosylation of DRP1 does not increase GTPase activity or cause dimerization. In fact, DRP1 does not exist as a dimer under nat...
Diabetes, Obesity and Metabolism, 2010
Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also c... more Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also converts into toxic radical species that can damage cells through a process known as nitrosative stress. While the physiological roles of NO in blood vessel dilation, the nervous system and the immune system are well established, recent studies have begun to investigate the role of NO in metabolism and energy expenditure through modulation of mitochondria. NO appears to stimulate mitochondrial biogenesis in certain situations through activation of proteins such as peroxisome proliferator-activated receptor γ (PPARγ ) co-activator 1α (PGC1-α). Because of this link between NO and mitochondrial biogenesis, the role of NO in certain aspects of metabolism, including exercise response, obesity, fat cell differentiation and caloric restriction, are the subject of increasing investigation. In addition to its role in mitochondrial biogenesis, NO also stimulates mitochondrial fragmentation, which can be caused by too much mitochondrial fission or inhibition of mitochondrial fusion and can result in bioenergetic failure. While the contribution of NO-mediated mitochondrial fragmentation to neurodegenerative diseases seems clear, the mechanisms by which NO causes fragmentation are uncertain and controversial. In this review, we discuss the role of NO in manipulation of mitochondrial biogenesis and dynamics and how these events contribute to human health-and age-related disease.
Cell Death and Differentiation, 2007
Diabetes, obesity & metabolism, 2010
Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also c... more Nitric oxide (NO) serves as a messenger molecule in a variety of physiological systems and also converts into toxic radical species that can damage cells through a process known as nitrosative stress. While the physiological roles of NO in blood vessel dilation, the nervous system and the immune system are well established, recent studies have begun to investigate the role of NO in metabolism and energy expenditure through modulation of mitochondria. NO appears to stimulate mitochondrial biogenesis in certain situations through activation of proteins such as peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC1-α). Because of this link between NO and mitochondrial biogenesis, the role of NO in certain aspects of metabolism, including exercise response, obesity, fat cell differentiation and caloric restriction, are the subject of increasing investigation. In addition to its role in mitochondrial biogenesis, NO also stimulates mitochondrial fragmentation, which can be caused by too much mitochondrial fission or inhibition of mitochondrial fusion and can result in bioenergetic failure. While the contribution of NO-mediated mitochondrial fragmentation to neurodegenerative diseases seems clear, the mechanisms by which NO causes fragmentation are uncertain and controversial. In this review, we discuss the role of NO in manipulation of mitochondrial biogenesis and dynamics and how these events contribute to human health- and age-related disease.
Antioxidants & Redox Signaling, 2009
Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a... more Nitric oxide (NO) is an important messenger molecule in a variety of physiological systems. NO, a gas, is produced from L-arginine by different isoforms of nitric oxide synthase (NOS) and serves many normal physiologic purposes, such as promoting vasodilation of blood vessels and mediating communication between nervous system cells. In addition to its physiologic actions, free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. Here, we review the role of NO in health and disease, focusing on its role in function and dysfunction of the nervous system. Substantial evidence indicates that NO plays a key role in most common neurodegenerative diseases, and, although the mechanism of NO-mediated neurodegeneration remains uncertain, studies suggest several possibilities. NO has been shown to modify protein function by nitrosylation and nitrotyrosination, contribute to glutamate excitotoxicity, inhibit mitochondrial respiratory complexes, participate in organelle fragmentation, and mobilize zinc from internal stores. In this review, we discuss and analyze the evidence for each of these mechanisms in different neurodegenerative diseases and propose future directions for research of the role of NO in neurodegeneration. Antioxid. Redox Signal. 11, 541-553.
Annals of the New York Academy of Sciences, 2008
Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, ... more Mitochondrial dysfunction is a common characteristic of all neurodegenerative diseases. However, the cause of this dysfunction remains a mystery. Here, we discuss the potential role of mitochondrial fission and fusion in the onset and progression of neurodegenerative diseases. Specifically, we propose that an imbalance in mitochondrial fission and fusion may underlie both familial and sporadic neurodegenerative disorders. There is substantial evidence that links disruption of the mitochondrial fission and fusion equilibrium, resulting in abnormally long or short mitochondria, to neurodegeneration. First, hereditary mutations in the mitochondrial fusion GTPases optic atrophy-1 and mitofusin-2 cause neuropathies in humans. In addition, recent findings report increased mitochondrial fission in Parkinson's disease (PD) models and induction of mitochondrial fission by two proteins, PTEN-induced kinase 1 and parkin, which are mutant in familial forms of PD. Furthermore, mutant huntingtin, the disease-causing protein in Huntington's disease, alters mitochondrial morphology and dynamics. Rotenone, a pesticide and inducer of PD symptoms, and amyloid-β peptide, which is causally linked to Alzheimer's disease, initiate mitochondrial fission. Finally, mitochondrial fission is an early event in ischemic stroke and diabetic neuropathies. In sum, a growing body of research suggests that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments and cures for neurodegenerative diseases.
Methods, 2008
Mitochondrial morphology and length change during fission and fusion and mitochondrial movement v... more Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microcopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.
Trends in Neurosciences, 2008
Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that gradually robs aff... more Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills, and normal movements. While research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key role in HD pathogenesis. Here, we highlight how mtHtt might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, membrane potential and Ca 2+ buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which in turn might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria may dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.
Nature Reviews Neuroscience, 2008
Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochond... more Mitochondria are remarkably dynamic organelles that migrate, divide and fuse. Cycles of mitochondrial fission and fusion ensure metabolite and mitochondrial DNA (mtDNA) mixing and dictate organelle shape, number and bioenergetic functionality. There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Mutations in mitochondrial fusion GTPases (mitofusin-2 and optic atrophy-1), neurotoxins and oxidative stress all disrupt the cable-like morphology of functional mitochondria. This results in impaired TOC Blurb: There is mounting evidence that mitochondrial dysfunction is an early and causal event in neurodegeneration. Here, Bossy-Wetzel and colleagues discuss how aberrant mitochondrial fission and fusion can contribute to neurodegenerative disease.
Cell death and differentiation, 2007