Short Mitochondrial ARF Triggers Parkin/PINK1-dependent Mitophagy

Parkinson disease (PD) is a complex neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Multiple genes have been associated with PD, including Parkin and PINK1. Recent studies have established that the Parkin and PINK1 proteins function in a common mitochondrial quality control pathway, whereby disruption of the mitochondrial membrane potential leads to PINK1 stabilization at the mitochondrial outer surface. PINK1 accumulation leads to Parkin recruitment from the cytosol, which in turn promotes the degradation of the damaged mitochondria by autophagy (mitophagy). Most studies characterizing PINK1/Parkin mitophagy have relied on high concentrations of chemical uncouplers to trigger mitochondrial depolarization, a stimulus that has been difficult to adapt to neuronal systems and one unlikely to faithfully model the mitochondrial damage that occurs in PD. Here, we report that the short mitochondrial isoform of ARF (smARF), previously identified as an alternate translation product of the tumor suppressor p19ARF, depolarizes mitochondria and promotes mitophagy in a Parkin/PINK1-dependent manner, both in cell lines and in neurons. The work positions smARF upstream of PINK1 and Parkin and demonstrates that mitophagy can be triggered by intrinsic signaling cascades.     

Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson’s Disease

Parkinson’s disease (PD) is the most common neurological movement disorder characterized by the selective and irreversible loss of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. While most cases are sporadic or environmental, about 10% of patients have a positive family history with a genetic cause. The misfolding and aggregation of α-synuclein (α-syn) as a casual factor in the pathogenesis of PD has been supported by a great deal of literature. Extensive studies of mechanisms underpinning degeneration of the dopaminergic neurons induced by α-syn dysfunction suggest a complex process that involves multiple pathways, including mitochondrial dysfunction and increased oxidative stress, impaired calcium homeostasis through membrane permeabilization, synaptic dysfunction, impairment of quality control systems, disruption of microtubule dynamics and axonal transport, endoplasmic reticulum/Golgi dysfunction, nucleus malfunction, and microglia activation leading to neuroinflammation. Among them mitochondrial dysfunction has been considered as the most primary target of α-syn-induced toxicity, leading to neuronal cell death in both sporadic and familial forms of PD. Despite reviewing many aspects of PD pathogenesis related to mitochondrial dysfunction, a systemic study on how α-syn malfunction/aggregation damages mitochondrial functionality and leads to neurodegeneration is missing in the literature. In this review, we give a detailed molecular overview of the proposed mechanisms by which α-syn, directly or indirectly, contributes to mitochondrial dysfunction. This may provide valuable insights for development of new therapeutic approaches in relation to PD. Antioxidant-based therapy as a potential strategy to protect mitochondria against oxidative damage, its challenges, and recent developments in the field are discussed.     

PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity

Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an age-dependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.     

Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification

Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.     

New insights into the role of mitochondrial dysfunction and protein aggregation in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative movement disorder that affects increasing number of elderly in the world population. The disease is caused by a selective degeneration of dopaminergic neurons in the substantia nigra pars compacta with the molecular mechanism underlying this neurodegeneration still not fully understood. However, various studies have shown that mitochondrial dysfunction and abnormal protein aggregation are two of the major contributors for PD. In fact this notion has been supported by recent studies on genes that are linked to familial PD (FPD). For instance, FPD linked gene products such as PINK1 and parkin have been shown to play critical roles in the quality control of mitochondria, whereas α-synuclein has been found to be the major protein aggregates accumulated in PD patients. These findings suggest that further understanding of how dysfunction of these pathways in PD will help develop new approaches for the treatment of this neurodegenerative disorder.     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质--多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

帕金森病黑质多巴胺神经元易损伤性的内在因素

帕金森病（Parkinson’s disease,PD）主要症状是由中脑黑质致密部（substantia nigra compact,SNc）的多巴胺（dopamine,DA）神经元死亡引起。帕金森病发病过程中,路易小体病理（Lewy pathology,LP）和线粒体功能障碍最为突出,但SNc 多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc 多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc 多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc 多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1-3钙通道活动及后续的级联反应增加了SNc 多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc 多巴胺神经元特有的神经递质——多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc 多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc 多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。     

Mitochondrial Quality Control and Parkinson’s Disease: A Pathway Unfolds

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.     

Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy

Parkinson disease is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. α-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of α-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T α-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T α-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models.     

Removing dysfunctional mitochondria from axons independent of mitophagy under pathophysiological conditions

Chronic mitochondrial dysfunction has been implicated in major neurodegenerative diseases. Long-term cumulative pathological stress leads to axonal accumulation of damaged mitochondria. Therefore, the early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. We recently investigated the axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in amyotrophic lateral sclerosis (ALS)- and Alzheimer disease (AD)-linked neurons. We demonstrated that remobilizing stressed mitochondria is critical for maintaining axonal mitochondrial integrity. The selective release of the mitochondrial anchoring protein SNPH (syntaphilin) from stressed mitochondria enhances their retrograde transport toward the soma before PARK2/Parkin-mediated mitophagy is activated. This SNPH-mediated response is robustly activated during the early disease stages of ALS-linked motor neurons and AD-related cortical neurons. Our study thus reveals a new mechanism for the maintenance of axonal mitochondrial integrity through SNPH-mediated coordination of mitochondrial stress and motility that is independent of mitophagy.     

Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild‐type but not PD‐linked mutant parkin supports the biogenesis of a population of mitochondria‐derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin‐ and PINK1‐dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.     

Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons

Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function. Translocation of Parkin to damaged mitochondria induces mitophagy in many nonneuronal cell types. However, evidence showing Parkin translocation in primary neurons is controversial, leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Δψ(m)-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with nonneuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondrial transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring-like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport.     

Acute dosing of latrepirdine (Dimebon™), a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo

Background

It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria supply the adenosine triphosphate (ATP) needed to support axonal transport and contribute to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer controls (CNT). The absorption of low level, near-infrared laser light by components of the mitochondrial electron transport chain (mtETC) enhances mitochondrial metabolism, stimulates oxidative phosphorylation and improves redox capacity. PD and CNT cybrid neuronal cells were exposed to near-infrared laser light to determine if the velocity of mitochondrial movement can be restored by low level light therapy (LLLT). Axonal transport of labeled mitochondria was documented by time lapse microscopy in dopaminergic PD and CNT cybrid neuronal cells before and after illumination with an 810 nm diode laser (50 mW/cm²) for 40 seconds. Oxygen utilization and assembly of mtETC complexes were also determined.

Results

The velocity of mitochondrial movement in PD cybrid neuronal cells (0.175 +/- 0.005 SEM) was significantly reduced (p < 0.02) compared to mitochondrial movement in disease free CNT cybrid neuronal cells (0.232 +/- 0.017 SEM). For two hours after LLLT, the average velocity of mitochondrial movement in PD cybrid neurites was significantly (p < 0.003) increased (to 0.224 +/- 0.02 SEM) and restored to levels comparable to CNT. Mitochondrial movement in CNT cybrid neurites was unaltered by LLLT (0.232 +/- 0.017 SEM). Assembly of complexes in the mtETC was reduced and oxygen utilization was altered in PD cybrid neuronal cells. PD cybrid neuronal cell lines with the most dysfunctional mtETC assembly and oxygen utilization profiles were least responsive to LLLT.

Conclusion

The results from this study support our proposal that axonal transport is reduced in sporadic PD and that a single, brief treatment with near-infrared light can restore axonal transport to control levels. These results are the first demonstration that LLLT can increase axonal transport in model human dopaminergic neuronal cells and they suggest that LLLT could be developed as a novel treatment to improve neuronal function in patients with PD.     

Insights into amyloid-β-induced mitochondrial dysfunction in Alzheimer disease

Amyloid-β has long been implicated in the pathogenesis of Alzheimer disease. The focus was initially on the extracellular fibrillar deposits of amyloid-β but more recently has shifted to intracellular oligomeric forms of amyloid-β. Unfortunately, the mechanism(s) by which either extracellular or intracellular amyloid-β induces neuronal toxicity remains unclear. That said, a number of recent studies indicate that mitochondria might be an important target of amyloid-β. Neurons rely heavily on mitochondria for energy and it is well established that mitochondrial dysfunction might be an important target of amyloid-β. Mechanistically, amyloid-β aggregates in mitochondria to impair function, leading to energy hypometabolism and elevated reactive oxygen species production. Additionally, amyloid-β affects the balance of mitochondrial fission/fusion and mitochondrial transport, negatively impacting a host of cellular functions of neurons. Here, we review the role that amyloid-β plays in mitochondrial structure and function of neurons and the importance of this in the pathogenesis of Alzheimer disease.     

Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: Implications for mitochondrial dysfunction in Parkinson disease

Oxidative stress and mitochondrial dysfunction, especially at the level of complex I of the electronic transport chain, have been proposed to be involved in the pathogenesis of Parkinson disease (PD). A plausible source of oxidative stress in nigral dopaminergic neurons is the redox reactions that specifically involve dopamine (DA) and produce various toxic molecules, i.e., free radicals and quinone species (DAQ). It has been shown that DA oxidation products can induce various forms of mitochondrial dysfunction, such as mitochondrial swelling and decreased electron transport chain activity. In the present work, we analyzed the potentially toxic effects of DAQ on mitochondria and, specifically, on the NADH and GSH pools. Our results demonstrate that the generation of DAQ in isolated respiring mitochondria triggers the opening of the permeability transition pore most probably by inducing oxidation of NADH, while GSH levels are not affected. We then characterized in vitro, by UV and NMR spectroscopy, the reactivity of different DA-derived quinones, i.e., dopamine-o-quinone (DQ), aminochrome (AC) and indole-quinone (IQ), toward NADH and GSH. Our results indicate a very diverse reactivity for the different DAQ studied that may contribute to unravel the complex molecular mechanisms underlying oxidative stress and mitochondria dysfunction in the context of PD.     

Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the leading causes of genetically inherited Parkinson's disease (PD) identified so far. The underlying mechanism whereby missense alterations in LRRK2 initiate neurodegeneration remains largely unclear. Mitochondrial dysfunction has been recognized to contribute to the pathogenesis of both sporadic and familial PD. The pathogenic gain-of-function mutant form of LRRK2, LRRK2 G2019S, is associated with elevated kinase activity and PD. Here we show that LRRK2 G2019S can cause defects in the morphology and dynamics of mitochondria in cortical neurons. In neurons, endogenous LRRK2 and the mitochondrial fission factor Dynamin like protein 1 (DLP1) interact with and partially co-localize with each other. DLP1 plays an essential role in LRRK2-induced mitochondrial fission. In support of this, expression of LRRK2 leads to the translocation of DLP1 from the cytosol to the mitochondria and knockdown of DLP1 expression inhibits LRRK2-induced mitochondrial fission. In addition, co-expression of LRRK2 and DLP1 induces mitochondrial clearance. Furthermore, we have found that expression of LRRK2 leads to increased reactive oxygen species levels in cells. Taken together, our results provide insights into the pathobiology of LRRK2 and suggest that LRRK2 G2019S may induce neuronal dysfunction or cell death by disturbing normal mitochondrial fission/fusion dynamics and function.     

Mitochondrial quality control: insights on how Parkinson’s disease related genes PINK1, parkin,and Omi/HtrA2 interact to maintain mitochondrial homeostasis

Alterations in mitochondrial homeostasis have been implicated in the etiology of Parkinson disease (PD) as demonstrated by human tissue studies, cell culture and in vivo genetic and toxin models. Mutations in the genes encoding PTEN-induced kinase 1 (PINK1), Omi/HtrA2 and parkin contribute to rare forms of parkinsonian neurodegeneration. Recently, each of these proteins has been shown to play a normal role in regulating mitochondrial structure, function, fission-fusion dynamics, or turnover (autophagy and biogenesis), promoting neuronal survival. Here, we review the biochemical mechanisms of mitochondrial protection conferred by each of these PD associated gene products in neurons, neuronal cell lines and other cell types. Potential molecular interactions and mitoprotective signaling pathways involving these three PD associated gene products are discussed in the context of mitochondrial quality control, in response to increasing levels of mitochondrial damage. We propose that PINK1, Omi/HtrA2 and parkin participate at different levels in mitochondrial quality control, converging through some overlapping and some distinct steps to maintain a common phenotype of healthy mitochondrial networks.     

Parkinson's disease: mechanisms and models

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.     

Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction

Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson's disease (PD) and expanding evidences demonstrate that an altered balance in mitochondrial fission/fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction/degeneration. In this study, we investigated whether DJ-1 is involved in the regulation of mitochondrial dynamics and function in neuronal cells. Confocal and electron microscopic analysis demonstrated that M17 human neuroblastoma cells over-expressing wild-type DJ-1 (WT DJ-1 cells) displayed elongated mitochondria while M17 cells over-expressing PD-associated DJ-1 mutants (R98Q, D149A and L166P) (mutant DJ-1 cells) showed significant increase of fragmented mitochondria. Similar mitochondrial fragmentation was also noted in primary hippocampal neurons over-expressing PD-associated mutant forms of DJ-1. Functional analysis revealed that over-expression of PD-associated DJ-1 mutants resulted in mitochondria dysfunction and increased neuronal vulnerability to oxidative stress (H(2) O(2)) or neurotoxin. Further immunoblot studies demonstrated that levels of dynamin-like protein (DLP1), also known as Drp1, a regulator of mitochondrial fission, was significantly decreased in WT DJ-1 cells but increased in mutant DJ-1 cells. Importantly, DLP1 knockdown in these mutant DJ-1 cells rescued the abnormal mitochondria morphology and all associated mitochondria/neuronal dysfunction. Taken together, these studies suggest that DJ-1 is involved in the regulation of mitochondrial dynamics through modulation of DLP1 expression and PD-associated DJ-1 mutations may cause PD by impairing mitochondrial dynamics and function.     

Insights into amyloid-beta-induced mitochondrial dysfunction in Alzheimer disease

Amyloid-β has long been implicated in the pathogenesis of Alzheimer disease. The focus was initially on the extracellular fibrillar deposits of amyloid-β but more recently has shifted to intracellular oligomeric forms of amyloid-β. Unfortunately, the mechanism(s) by which either extracellular or intracellular amyloid-β induces neuronal toxicity remains unclear. That said, a number of recent studies indicate that mitochondria might be an important target of amyloid-β. Neurons rely heavily on mitochondria for energy and it is well established that mitochondrial dysfunction might be an important target of amyloid-β. Mechanistically, amyloid-β aggregates in mitochondria to impair function, leading to energy hypometabolism and elevated reactive oxygen species production. Additionally, amyloid-β affects the balance of mitochondrial fission/fusion and mitochondrial transport, negatively impacting a host of cellular functions of neurons. Here, we review the role that amyloid-β plays in mitochondrial structure and function of neurons and the importance of this in the pathogenesis of Alzheimer disease.