Mitochondria are key cell organelles in that they are responsible for energy production and control many processes from signalling to cell death. The function of the mitochondrial electron transport ...chain is coupled with the production of reactive oxygen species (ROS) in the form of superoxide anion or hydrogen peroxide. As a result of the constant production of ROS, mitochondria are protected by highly efficient antioxidant systems. The rapidly changing levels of ROS in mitochondria, coupled with multiple essential cellular functions, make ROS apt for physiological signalling. Thus, mutations, environmental toxins and chronic ischaemic conditions could affect the mitochondrial redox balance and lead to the development of pathology. In long‐living and non‐mitotic cells such as neurons, oxidative stress induced by overproduction of mitochondrial ROS or impairment of the antioxidant defence results in a dysfunction of mitochondria and initiation of the cell death cascade. Mitochondrial ROS overproduction and changes in mitochondrial redox homeostasis have been shown to be involved in both a number of neurological conditions and a majority of neurodegenerative diseases. Here, we summarise the involvement of mitochondrial ROS in the mechanism of neuronal loss of major neurodegenerative disorders.
Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. ...Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD.
Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has ...emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
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•The transcription factor Nrf2 is regulator of mitochondrial function.•Nrf2 control energy homeostasis in cells.•Nrf2 involved in mitochondrial quality control and structure.•Nrf2 is regulates mitochondrial redox signal and cell death initiation.
The major energy generator in the cell – mitochondria produce reactive oxygen species as a by-product of a number of enzymatic reactions and the production of ATP. Emerging evidence suggests that ...mitochondrial ROS regulate diverse physiological parameters and that dysregulated ROS signalling may contribute to a development of processes which lead to human diseases. ROS produced in mitochondrial enzymes are triggers of monoamine-induced calcium signal in astrocytes, playing important role in physiological and pathophysiological response to dopamine. Generation of ROS in mitochondria leads to peroxidation of lipids, which is considered to be one of the most important mechanisms of cell injury under condition of oxidative stress. However, it also can induce activation of mitochondrial and cellular phospholipases that can trigger a variety of the signals – from activation of ion channels to stimulation of calcium signal. Mitochondria are shown to be the oxygen sensor in astrocytes, therefore inhibition of respiration by hypoxia induces ROS production which leads to lipid peroxidation, activation of phospholipase C and induction of IP3-mediated calcium signal. Propagation of astrocytic calcium signal stimulates breathing activity in response to hypoxia. Thus, ROS produced by mitochondrial enzymes or electron transport chain can be used as a trigger for signalling cascades in central nervous system and deregulation of this process leads to pathology.
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•Mitochondria produce and modify ROS in response to physical and chemical stimuli.•Mitochondria are able to sense changes in atmospheric O2 and produce ROS to hypoxia.•Mitochondrial ROS can induce lipid peroxidation and activate PLC-induced Ca2+ signal.•Superoxide from mitochondria can modify activity of ion channels and receptors.
The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of ...cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress.
•Nrf2 has a crucial role in maintaining cellular redox homeostasis.•Nrf2 affects the mitochondrial membrane potential and ATP synthesis.•Nrf2 influences mitochondrial fatty acid oxidation.•Nrf2 supports the structural and functional integrity of the mitochondria.•Nrf2 activators have beneficial effects when mitochondrial function is compromised.
In this special interview series, we profile members of The FEBS Journal editorial board to highlight their research focus, perspectives on the journal and future directions in their field. Professor ...Andrey Abramov is a cell biologist and biophysicist at University College London's Queen Square Institute of Neurology. He has served as an Editorial Board Member of The FEBS Journal since 2015.
The world's population aging progression renders age‐related neurodegenerative diseases to be one of the biggest unsolved problems of modern society. Despite the progress in studying the development ...of pathology, finding ways for modifying neurodegenerative disorders remains a high priority. One common feature of neurodegenerative diseases is mitochondrial dysfunction and overproduction of reactive oxygen species, resulting in oxidative stress. Although lipid peroxidation is one of the markers for oxidative stress, it also plays an important role in cell physiology, including activation of phospholipases and stimulation of signaling cascades. Excessive lipid peroxidation is a hallmark for most neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and many other neurological conditions. The products of lipid peroxidation have been shown to be the trigger for necrotic, apoptotic, and more specifically for oxidative stress‐related, that is, ferroptosis and neuronal cell death. Here we discuss the involvement of lipid peroxidation in the mechanism of neuronal loss and some novel therapeutic directions to oppose it.
Oxidative stress and alteration of redox signaling is shown to be involved in the mechanism of neuronal loss in the most of neurodegenerative diseases. This Special Issue features seven review ...articles that cover major aspects of the changes of redox biology in the mechanism of pathology of neurodegenerative diseases and discusses possible ways for prevention.
Biological tissues require oxygen to meet their energetic demands. However, the consumption of oxygen also results in the generation of free radicals that may have damaging effects on cells. The ...brain is particularly vulnerable to the effects of reactive oxygen species due to its high demand for oxygen, and its abundance of highly peroxidisable substrates. Oxidative stress is caused by an imbalance in the redox state of the cell, either by overproduction of reactive oxygen species, or by dysfunction of the antioxidant systems. Oxidative stress has been detected in a range of neurodegenerative disease, and emerging evidence from in vitro and in vivo disease models suggests that oxidative stress may play a role in disease pathogenesis. However, the promise of antioxidants as novel therapies for neurodegenerative diseases has not been borne out in clinical studies. In this review, we critically assess the hypothesis that oxidative stress is a crucial player in common neurodegenerative disease and discuss the source of free radicals in such diseases. Furthermore, we examine the issues surrounding the failure to translate this hypothesis into an effective clinical treatment.
The brain is the organ that orchestrates the whole body. To do so, neurons and glia in different brain regions have evolved to be highly specialized and are regulated by diverse receptors and neuro‐ ...and gliotransmitters. Some of the features of the brain, including a protective brain–blood barrier, high‐energy demand, and electrical activity, mean that neurons and astrocytes are uniquely diverse components of tissue that vary greatly even across brain regions. This Special Issue features 19 review articles that cover different aspects of the broad field of neuroscience—from neurodevelopment, physiology and memory formation to the mechanisms underlying the development of neurodegenerative diseases.
In this Editorial, the contents of a Special Issue on Neurobiology are described by Andrey Abramov. The Special Issue features nineteen review articles that cover different aspects of the broad field of neuroscience from neurodevelopment, physiology, and memory formation to the mechanisms underlying the development of neurodegenerative diseases. We hope that readers will find these reviews interesting and informative.
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