The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain

The consumption of flavonoid-rich foods and beverages has been suggested to limit the neurodegeneration associated with a variety of neurological disorders and to prevent or reverse normal or abnormal deteriorations in cognitive performance. Flavonoids mediate these effects via a number of routes, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation and a potential to promote memory, learning and cognitive function. Originally, it was thought that such actions were mediated by the antioxidant capacity of flavonoids. However, their limited absorption and their low bioavailability in the brain suggest that this explanation is unlikely. Instead, this multiplicity of effects appears to be underpinned by three separate processes: first, through their interactions with important neuronal and glial signalling cascades in the brain, most notably the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways that regulate pro-survival transcription factors and gene expression; second, through an ability to improve peripheral and cerebral blood flow and to trigger angiogenesis and neurogenesis in the hippocampus; third, by their capacity to directly react with and scavenge neurotoxic species and pro-inflammatory agents produced in the brain as a result of both normal and abnormal brain ageing. The present review explores the potential inhibitory or stimulatory actions of flavonoids within these three systems and describes how such interactions are likely to underlie neurological effects

Investigating the effects of the microglial inflammatory response on iron metabolism in dopaminergic neurons

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterised by selective loss of dopaminergic neurons in the substantia nigra. Drugs are the principal method of symptom treatment, yet remain unable to reverse underlying neurodegeneration. As PD prevalence increases with aging populations, greater emphasis falls on understanding pathogenesis to establish an effective neuroprotective strategy. Current research identifies iron accretion as a potential pathogenic factor. Iron is crucial for healthy cellular physiology, however, dysregulation can be highly neurotoxic. Since iron cannot be excreted, levels must be tightly controlled via specific iron regulatory proteins (IRP), including hepcidin, transferrin receptors, divalent metal transporter 1, ferritin, ferroportin, aconitase 1, and iron response element-binding protein 2. Iron accumulation has been established in neurodegenerative diseases, including Alzheimer’s, Multiple Sclerosis, and PD. While the instigating causes remain unknown, inflammation is a common factor. Activated microglia mediate the inflammatory response, and can release cytotoxic substances leading to iron-induced toxicity. Since dopaminergic neurons in PD are vulnerable to iron overload and inflammation, it is vital to determine what promotes changes to IRP expression leading to iron accumulation. It is hypothesised that chronic microglial activation and ensuing pro-inflammatory factors can dysregulate neuronal iron. Such changes may result from alterations in key IRP gene expression, with downstream cascades leading to neuronal degeneration. Results herein provide evidence of microglial inflammatory factor involvement on neuronal iron metabolism in an in vitro model of dopaminergic neurons. Specifically, IL6, TNF and new evidence of hydrogen peroxide instigate significant alterations in expression of HAMP, TfR and DMT1, causing iron elevations. Co-culture experiments established astrocytic iron buffering mechanisms able to provide sufficient neuroprotection to abolish observed gene expression changes. Lastly, experiments conclude that neuronal death occurs mainly via apoptotic pathways. Collectively, results support the instigative role of inflammation on altering neuronal iron handling. Such discoveries could lead to potential improvements in therapeutic strategies for PD.Open Acces

Reactive Oxygen Species

The term “reactive oxygen species” (ROS) refers to a group of reactive molecules and free radicals produced by molecular oxygen. In recent decades, there has been great interest in the role of ROS in various diseases. From basic science research to clinical trials, biomedical scientists have made rapid progress toward a better understanding of ROS-metabolizing systems and their role in health and diseases. This book includes sixteen chapters that address topics such as the history of ROS, its role in autoimmunity, neurodegeneration, and aging, and recent advances in various antioxidants and their therapeutic potential

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity

Apoptotic interactions of cytochrome c: Redox flirting with anionic phospholipids within and outside of mitochondria

AbstractSince the (re)discovery of cytochrome c (cyt c) in the early 1920s and subsequent detailed characterization of its structure and function in mitochondrial electron transport, it took over 70 years to realize that cyt c plays a different, not less universal role in programmed cell death, apoptosis, by interacting with several proteins and forming apoptosomes. Recently, two additional essential functions of cyt c in apoptosis have been discovered that are carried out via its interactions with anionic phospholipids: a mitochondria specific phospholipid, cardiolipin (CL), and plasma membrane phosphatidylserine (PS). Execution of apoptotic program in cells is accompanied by substantial and early mitochondrial production of reactive oxygen species (ROS). Because antioxidant enhancements protect cells against apoptosis, ROS production was viewed not as a meaningless side effect of mitochondrial disintegration but rather playing some – as yet unidentified – role in apoptosis. This conundrum has been resolved by establishing that mitochondria contain a pool of cyt c, which interacts with CL and acts as a CL oxygenase. The oxygenase is activated during apoptosis, utilizes generated ROS and causes selective oxidation of CL. The oxidized CL is required for the release of pro-apoptotic factors from mitochondria into the cytosol. This redox mechanism of cyt c is realized earlier than its other well-recognized functions in the formation of apoptosomes and caspase activation. In the cytosol, released cyt c interacts with another anionic phospholipid, PS, and catalyzes its oxidation in a similar oxygenase reaction. Peroxidized PS facilitates its externalization essential for the recognition and clearance of apoptotic cells by macrophages. Redox catalysis of plasma membrane PS oxidation constitutes an important redox-dependent function of cyt c in apoptosis and phagocytosis. Thus, cyt c acts as an anionic phospholipid specific oxygenase activated and required for the execution of essential stages of apoptosis. This review is focused on newly discovered redox mechanisms of complexes of cyt c with anionic phospholipids and their role in apoptotic pathways in health and disease

Cell Death Mechanisms in Drosophila Differentiated Photoreceptor Neurons

Apoptosis, or programmed cell death, is a form of physiological cell death that is essential for normal development and homeostasis. At the end of pupal development of the Drosophila retina, cell death terminates and photoreceptor neurons complete their differentiation process. We use these terminally differentiated photoreceptor neurons as a system to study neurodegeneration. We first adapt and develop fluorescent tools for photoreceptor visualization in vivo. These tools enable a recessive genetic screen to search for genes required for the survival of differentiated photoreceptors. Many redox and mitochondrial genes were found to protect photoreceptors from late cell death. Here, we focus on the iron-storage complex, Ferritin. ferritin mutations lead to caspase activation and photoreceptor neuronal death during development and sensitize adult photoreceptor neurons to cell death stimuli. ferritin mutations provide a robust model to study the role of iron and oxidative stress in neurodegeneration. To further investigate the role of Ferritin in photoreceptor survival, we generate genetically-encoded in vivo iron and redox sensors. In summary, by developing novel tools for photoreceptor cell visualization, we explore the neuro-specific mechanisms required for lifelong photoreceptor neuron survival. We perform a photoreceptor-specific genetic screen and characterize Ferritin’s role in shielding photoreceptor cells from iron and oxidative stress-induced cell death

Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease

Alzheimer diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Aβ deposits in senile plaque and neurofibrillary tangles (NFT), are strongly intertwined with reactive oxygen species (ROS)production and oxidative stress (OS),which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions