| Supplemental Issue "Mitochondria and Neurodegenerative Diseases " (Guest Editors: Xiongwei Zhu, M. Flint Beal, Xinglong Wang, George Perry, Mark A. Smith), June 2010
Page 253
Xiongwei Zhu, M. Flint Beal, Xinglong Wang, George Perry, Mark A. Smith
Preface: Mitochondria and Neurodegenerative Diseases
Pages 255-263
Review
Vanessa A. Morais and Bart De Strooper
Mitochondria Dysfunction and Neurodegenerative Disorders: Cause or Consequence
Abstract: Mitochondria are crucial regulators of energy metabolism and apoptotic pathways and have been closely linked to the pathogenesis of neurodegenerative disorders. In this review we mainly focus on mitochondrial dysfunction in two of the most prevalent neurological disorders: Alzheimer’s disease and Parkinson’s disease. We discuss whether the role of mitochondria in those diseases should be considered primordial or secondary to other processes that eventually lead to neurodegeneration. In the case of Parkinson’s disease, the role of mitochondria is quite clear and might be involved in the mechanism of this disorder. For Alzheimer’s disease, the evidence in favor of such a link is more indirect, and mitochondrial dysfunction likely occurs at a later stage of the disorder.
Pages 265-279
Review
Russell H. Swerdlow, Jeffrey M. Burns, Shaharyar M. Khan
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Abstract: We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer’s disease (AD) in 2004. Our core assumptions were a person’s genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-β (Aβ) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Aβ thus far have had at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD.
Pages 281-292
Review
Eric A. Schon, Estela Area-Gomez
Is Alzheimer’s Disease a Disorder of Mitochondria-Associated Membranes?
Abstract: The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer’s disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM)—a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria—is the predominant subcellular location for PS1 and PS2, and for g-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.
Pages 293-310
Original Contribution
Pinar E. Coskun, Joanne Wyrembak, Olga Derbereva, Goar Melkonian, Eric Doran, Ira T. Lott, Elizabeth Head, Carl W. Cotman, Douglas C. Wallace
Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer’s Disease and Down Syndrome Dementia
Abstract: Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer’s disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-β peptide (Aβ40 and Aβ42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with β-secretase activity and mtDNA copy number is inversely correlated with insoluble Aβ40 and Aβ42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.
Pages 311-324
Review
Ping Shi, Yanming Wei, Jiayu Zhang, Jozsef Gal, Haining Zhu
Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis
Abstract: A better understanding of the etiology of amyotrophic lateral sclerosis (ALS) is needed to develop effective therapies for the treatment of this fatal neurodegenerative disease. Extensive studies have produced a general agreement that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology, and aberrant RNA metabolism. Mitochondria have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules is disrupted in ALS. Furthermore, new evidence suggests that mitochondrial fission and fusion as well as mitophagy clearance may also be affected by mutant SOD1. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging “dying-back” axonopathy model of ALS. In this review, we will discuss findings supporting that mitochondrial dysfunction is likely to be a converging point of multiple pathways underlying the ALS pathogenesis and progression.
Pages 325-334
Review
Jianhui Zhu and Charleen T. Chu
Mitochondrial Dysfunction in Parkinson’s Disease
Abstract: It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson’s disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including α-synuclein, PTEN-induced kinase 1, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss of function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health.
Pages 335-356
Review
Lee J. Martin
Mitochondrial Pathobiology in Parkinson’s Disease and Amyotrophic Lateral Sclerosis
Abstract: Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the second and third most common human adult-onset neurodegenerative diseases, respectively, after Alzheimer’s disease. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of PD and ALS are inherited, and genes causing these diseases have been identified. Morphological, biochemical, and genetic, as well as cell and animal model, studies reveal that mitochondria could have a role in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy.
Pages 357-367
Review
David A. Patten*, Marc Germain*, Melissa Kelly, Ruth S. Slack *These authors contributed equally to this work.
Reactive Oxygen Species: Stuck in the Middle of Neurodegeneration
Abstract: Neuronal cell loss associated with neurodegeneration has recently been linked to mitochondrial dysfunction. Electron transport chain defects and reactive oxygen species (ROS) production are emerging as important players in the etiology of neurodegenerative diseases. Proper management of ROS and disposal of damaged cellular components are vital to the survival and function of neurons. Proteins involved in these pathways are often mutated in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. In this review, we will discuss the roles of ROS in normal physiology, how changes in ROS production affect neuronal survival in neurodegenerative diseases, and the recent advances in mitochondrial antioxidants as potential therapeutics.
Pages 369-379
Review
Massimiliano Di Filippo, Davide Chiasserini, Alessandro Tozzi, Barbara Picconi, Paolo Calabresi
Mitochondria and the Link Between Neuroinflammation and Neurodegeneration
Abstract: The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of several different neurological diseases. Interestingly, it has been proposed that mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders. In this review, we describe the mechanisms by which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal death. In particular, we will describe the close relationship existing among neuroinflammation, neurodegeneration, and mitochondrial impairment in three different widely-diffused neurological diseases in which these pathogenetic events coexist, namely multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease.
Pages 381-400
Review
Kisha J Young, James P Bennett
The Mitochondrial Secret(ase) of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field’s understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.
Pages 401-412
Review
Renato X. Santos, Sónia C. Correia, Xinglong Wang, George Perry, Mark A. Smith, Paula I. Moreira, Xiongwei Zhu (Handling Editor: Jesus Avila)
A Synergistic Dysfunction of Mitochondrial Fission/Fusion Dynamics and Mitophagy in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD), the most common form of dementia in the elderly, can have a late-onset sporadic or an early-onset familial origin. In both cases, the neuropathological hallmarks are the same: senile plaques and neurofibrillary tangles. Despite AD having a proteinopathic nature, there is strong evidence for an organelle dysfunction-related neuropathology, namely dysfunctional mitochondria. In this regard, dysfunctional mitochondria and associated exacerbated generation of reactive oxygen species are among the earliest events in the progression of the disease. Since the maintenance of a healthy mitochondrial pool is essential given the central role of this organelle in several determinant cellular processes, mitochondrial dysfunction in AD would be predicted to have profound pluripotent deleterious consequences. Mechanistically, recent reports suggest that mitochondrial fission/fusion and mitophagy are altered in AD and in in vitro models of disease, and since both processes are reported to be protective, this review will discuss the role of mitochondrial fission/fusion and mitophagy in the pathogenesis of AD.
Pages 413-426
Review
Vera Adam-Vizi, Anatoly A. Starkov
Calcium and Mitochondrial Reactive Oxygen Species Generation: How to Read the Facts
Abstract: A number of recent discoveries indicate that abnormal Ca2+ signaling, oxidative stress, and mitochondrial dysfunction are involved in the neuronal damage in Alzheimer’s disease. However, the literature on the interactions between these factors is controversial especially in the interpretation of the cause-effect relationship between mitochondrial damage induced by Ca2+ overload and the production of reactive oxygen species (ROS). In this review, we survey the experimental observations on the Ca2+-induced mitochondrial ROS production, explain the sources of controversy in interpreting these results, and discuss the different molecular mechanisms underlying the effect of Ca2+ on the ROS emission by brain mitochondria.
Pages 427-437
Review
Tiffany Greco, Gary Fiskum
Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression
Abstract: Oxidative stress and loss of cellular Ca2+ homeostasis are closely linked and are common denominators in the pathophysiology of many neurodegenerative diseases and acute disorders of the nervous system. Mitochondria are major targets of oxidative stress and abnormal intracellular Ca2+, as both can cause bioenergetic failure through synergistic activation of the mitochondrial inner membrane permeability transition pore. Opening of this molecularly ill-defined pore causes both collapse of the membrane potential, which drives oxidative phosphorylation, and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defense against oxidative stress. Expression of genes coding for many antioxidant defense proteins is regulated by the Nrf2 transcriptional activating factor. Translocation of this protein from the cytosol to the nucleus is stimulated by oxidative stress and by specific agents that either react with cysteine sulfhydryl groups present on the protein KEAP1, that normally binds and restricts Nrf2 translocation, or that stimulate serine phosphorylation of Nrf2. Recent evidence indicates that mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway can increase resistance to redox-regulated opening of the permeability transition pore. Pharmacologic stimulation of the Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury.
Pages 439-452
Review
Hani Atamna and Raj Kumar
Protective Role of Methylene Blue in Alzheimer’s Disease via Mitochondria and Cytochrome c Oxidase
Abstract: The key cytopathologies in the brains of Alzheimer’s disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of β species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed.
Pages 453-473
Review
Gavin C. Higgins, Philip M. Beart, Yea Seul Shin, Minghui Jessica Chen, Nam Sang Cheung, Phillip Nagley
Oxidative Stress: Emerging Mitochondrial and Cellular Themes and Variations in Neuronal Injury
Abstract: Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer’s disease, and other pathologies including Parkinson’s disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances.
Pages 475-485
Review
Sónia C. Correia, Renato X. Santos, George Perry, Xiongwei Zhu, Paula I. Moreira, Mark A. Smith (Handling Editor: Jesus Avila)
Mitochondria: The Missing Link Between Preconditioning and Neuroprotection
Abstract: The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon—a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration.
Pages 487-498
Review
Charlene Supnet and Ilya Bezprozvanny
Neuronal Calcium Signaling, Mitochondrial Dysfunction, and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder among the aged worldwide. AD is characterized by extensive synaptic and neuronal loss that leads to impaired memory and cognitive decline. The cause of AD is not completely understood and no effective therapy has been developed. The accumulation of toxic amyloid-β42 (Aβ42) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed ‘amyloid hypothesis’ of AD etiology. In addition to the increase in Aβ42 levels, disturbances in neuronal calcium (Ca2+) signaling and alterations in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these data, the ‘Ca2+ hypothesis of AD’ has been proposed. In particular, familial AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as activation of calcineurin and calpains. Here we review the latest results supporting the ‘Ca2+ hypothesis’ of AD pathogenesis. We further argue that over time, supranormal cytosolic Ca2+ signaling can impair mitochondrial function in AD neurons. We conclude that inhibitors and stablizers of neuronal Ca2+ signaling and mitochondrial function may have therapeutic potential for AD treatment. We also discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochondria.
Pages 499-512
Review
P. Hemachandra Reddy, Maria Manczak, Peizhong Mao, Marcus Calkins, Arubala P. Reddy, Ulzii Shirendeb
Amyloid-β and Mitochondria in Aging and Alzheimer’s Disease: Implications for Synaptic Damage and Cognitive Decline
Abstract: This article reviews the role of amyloid-β (Aβ) and mitochondria in synaptic damage and cognitive decline found in patients with Alzheimer’s disease (AD). Recent molecular, cellular, animal model, and postmortem brain studies have revealed that Aβ and mitochondrial abnormalities are key factors that cause synaptic damage and cognitive decline in AD. Aβ is reported to accumulate in subcellular compartments and to impair the normal function of neurons in AD patients. Further, recent studies using biochemical methods and electron microscopy have revealed that the accumulation of Aβ at nerve terminals affect synaptic activities, including the release of neurotransmitters and synaptic vesicles. Recent studies of the relationship between mitochondria and Aβ in AD patients suggest that in mitochondria, structural changes caused by Aβ result in increased mitochondrial fragmentation, decreased mitochondrial fusion, mitochondrial dysfunction, and synaptic damage. This paper discusses the latest research on Aβ, mitochondria, age-dependent factors of AD in the brain, and synaptic damage in AD. This paper also briefly discusses potential mitochondrial therapeutics in the treatment of patients with AD.
Pages 513-526
Original Contribution
Blaise Bossy, Alejandra Petrilli, Eva Klinglmayr, Jin Chen, Ursula Lütz-Meindl, Andrew B. Knott, Eliezer Masliah, Robert Schwarzenbacher, Ella Bossy-Wetzel
S-Nitrosylation of DRP1 Does Not Affect Enzymatic Activity and is Not Specific to Alzheimer’s Disease
Abstract: 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 native conditions, but rather as a tetramer capable of self-assembly into higher order spiral- and ring-like oligomeric structures after nucleotide binding. S-nitrosylation, as confirmed by the biotin-switch assay, has no impact on DRP1 oligomerization. Importantly, we found no significant difference in S-nitrosylated DRP1 (SNO-DRP1) levels in brains of age-matched normal, AD, or PD patients. We also found that S-nitrosylation is not specific to DRP1 because S-nitrosylated optic atrophy 1 (SNO-OPA1) is present at comparable levels in all human brain samples. Finally, we show that NO triggers DRP1 phosphorylation at serine 616, which results in its activation and recruitment to mitochondria. Our data indicate the mechanism underlying nitrosative stress-induced mitochondrial fragmentation in AD is not DRP1 S-nitrosylation.
Pages 527-533
Review
Jose Viña and Ana Lloret
Why Women Have More Alzheimer’s Disease Than Men: Gender and Mitochondrial Toxicity of Amyloid-β Peptide
Abstract: The main risk factors for developing Alzheimer’s disease (AD) are age and gender. The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-β toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females. Since estrogenic compounds protect against mitochondrial toxicity of amyloid-β, estrogenic action may be important in protecting cells from amyloid-β toxicity and suggests a possible treatment or prevention strategy for AD. Unfortunately, to date, clinical trials with Ginkgo biloba and other estrogenic therapies have not proved successful in treating AD. As such, more experiments and clinical trials are indeed warranted to find conditions in which estrogenic compounds may be useful to prevent or treat AD.
Pages 535-550
Original Contribution
Natasa Dragicevic, Malgorzata Mamcarz, Yuyan Zhu, Jun Tan, Gary W Arendash, Patrick C Bradshaw
Mitochondrial Amyloid-β Levels are Associated with the Extent of Mitochondrial Dysfunction in Different Brain Regions and the Degree of Cognitive Impairment in Alzheimer’s Transgenic Mice
Abstract: Mitochondrial dysfunction is observed in Alzheimer’s disease (AD) brain, and the amyloid-β (Aβ) peptide is known to induce mitochondrial dysfunction. The relative degree of mitochondrial dysfunction in different regions of the brain in AD is not completely understood. Moreover, the relationship between levels of synaptic mitochondrial Aβ and mitochondrial dysfunction has not been clearly established. Therefore synaptic and nonsynaptic mitochondria were isolated from the hippocampus, cortex, striatum, and amygdala of 12 month AβPPsw and AβPP+PS1 mouse models of AD as well as nontransgenic mice. Mitochondrial respiratory rates, reactive oxygen species production, membrane potential, and cytochrome c oxidase activity were measured. Hippocampal and cortical mitochondria showed the highest levels of mitochondrial dysfunction, while striatal mitochondria were moderately affected, and amygdalar mitochondria were minimally affected. Mitochondria from AβPP/PS1 brain regions were more impaired than those from AβPP mice. Mitochondrial Aβ levels nearly mirrored the extent of mitochondrial dysfunction. Synaptic mitochondria were more impaired than nonsynaptic mitochondria in the AD mouse models. The AβPP/PS1 mice showed more impairment in the cognitive interference task of working memory than the AβPP mice. The association between mitochondrial Aβ levels and mitochondrial dysfunction in mouse models of AD supports a primary role for mitochondrial Aβ in AD pathology. Moreover, the degree of cognitive impairment in AD transgenic mice can be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Aβ levels, suggesting that a mitochondrial Aβ-induced signaling cascade may contribute to cognitive impairment. Therapeutics that target this cascade could be beneficial in the treatment of AD.
Pages 551-568
Review
Maxx P. Horowitz and J. Timothy Greenamyre
Mitochondrial Iron Metabolism and Its Role in Neurodegeneration
Abstract: In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme—prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress—pathologies that are inter-related. This review discusses the physiological role that mitochondria play in cellular iron homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease.
Pages 569-578
Review
John Xi Chen, Shirley Shidu Yan
Role of Mitochondrial Amyloid-β in Alzheimer’s Disease
Abstract: Mitochondrial dysfunction is an early feature of Alzheimer’s disease (AD). Abnormalities in mitochondrial properties include impaired energy metabolism, defects in key respiratory enzyme activity/function, accumulation/generation of mitochondrial reactive oxygen species, and formation of membrane permeability transition pore. While the mechanisms underlying mitochondrial dysfunction remain incompletely understood, recent studies provide substantial evidence for the progressive accumulation of mitochondrial Aβ, which directly links to mitochondria-mediated toxicity. In this review, we describe recent studies addressing the following key questions: 1) Does Aβ accumulate in mitochondria of AD brain and AD mouse models?; 2) How does Aβ gain access to the mitochondria?; 3) If mitochondria are loaded with Aβ, do they develop similar evidence of dysfunction?; 4) What are the mechanisms underlying mitochondrial Aβ-induced neuronal toxicity?; and 5) What is the impact of interaction of mitochondrial Aβ with its binding partners (cyclophilin D and ABAD) on mitochondrial and neuronal properties/function in an Aβ milieu? The answers to these questions provide new insights into mechanisms of mitochondrial stress related to the pathogenesis of AD and information necessary for developing therapeutic strategy for AD.
Pages 579-590
Review
Maria Ankarcrona, Francesca Mangialasche, Bengt Winblad
Rethinking Alzheimer’s Disease Therapy: Are Mitochondria the Key?
Abstract: The number of people suffering from Alzheimer’s disease (AD) is constantly increasing worldwide since humans live longer and age is the strongest risk factor for AD. Currently available medications for AD do not interfere with the progressive loss of synapses and neurons in the AD brain. Therefore, the development of disease modifying therapies is a major future goal Mitochondria provide cellular energy and are crucial for proper neuronal activity and survival. Mitochondrial dysfunction is evident in early stages of AD and is involved in AD pathogenesis. The development of drugs that protect mitochondria from damage is therefore a promising strategy for AD therapy. In this review, we will discuss current available medications for AD, drugs under clinical testing, and mitochondria as a novel drug target.
Pages 591-607
Review
Gary E. Gibson and Qingli Shi
A Mitocentric View of Alzheimer’s Disease Suggests Multi-Faceted Treatments
Abstract: Alzheimer’s disease (AD) is defined by senile plaques made of amyloid-β peptide (Aβ), neurofibrillary tangles made of hyperphosphorylated tau proteins, and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g., genetic mutations lead to high Aβ1-42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in glucose metabolism/mitochondrial function/oxidative stress (GMO) are an invariant feature of AD and occur at an early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles, and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis, and cognition that comprise AD.
Pages 609-631
Original Contribution
Maria Manczak, Peizhong Mao, Marcus Calkins, Anda Cornea, Arubala P. Reddy, Michael P. Murphy, Hazel H. Szeto, Byung Park, P. Hemachandra Reddy
Mitochondria-Targeted Antioxidants Protect Against Amyloid-β Toxicity in Alzheimer’s Disease Neurons
Abstract: The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants, MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model (Tg2576 line) of Alzheimer’s disease (AD) and on mouse neuroblastoma (N2a) cells incubated with the amyloid-β (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes and also decreased expression of peroxiredoxins. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid-β precursor protein transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that MitoQ and SS31 prevent Aβ toxicity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.
Pages 633-643
Review
Magali Dumont, Michael T. Lin, M. Flint Beal
Mitochondria and Antioxidant Targeted Therapeutic Strategies for Alzheimer’s Disease
Abstract: Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer’s disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spices. However, their efficacy was much more modest in human trials. More recently, new strategies have been elaborated to promote endogenous antioxidant systems. Different pathways involved in oxidative stress response have been identified. Compounds able to upregulate these pathways are being generated and tested in animal models of AD and in human patients. Upregulation of antioxidant gene expression was beneficial in mice, giving hope for future avenues in the treatment of AD and other neurodegenerative disorders.
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