Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment.
TL;DR: The purpose of this review was to present the current status of the knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment.
Abstract: Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological-based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.
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TL;DR: Current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery, and the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches are promoted.
Abstract: Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.
285 citations
Cites background from "Mitochondrial Dysfunction and Bioge..."
...Most of the energy required by brain is provided by mitochondria, and sufficient energy is required for neuronal survival; therefore, mitochondrial dysfunction could result in neuronal death [16]....
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TL;DR: The intricate genotype–phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies are reviewed, revealing shared pathogenic mechanisms and emerging therapeutic opportunities and challenges.
Abstract: Neurodegenerative diseases cause progressive loss of cognitive and/or motor function and pose major challenges for societies with rapidly aging populations. Human genetics studies have shown that disease-causing rare mutations and risk-associated common alleles overlap in different neurodegenerative disorders. Here we review the intricate genotype-phenotype relationships and common cellular pathways emerging from recent genetic and mechanistic studies. Shared pathological mechanisms include defective protein quality-control and degradation pathways, dysfunctional mitochondrial homeostasis, stress granules, and maladaptive innate immune responses. Research efforts have started to bear fruit, as shown by recent treatment successes and an encouraging therapeutic outlook.
282 citations
TL;DR: A comprehensive look at how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors and how these organelles cooperate in various metabolic and signaling pathways is provided.
Abstract: Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease
223 citations
Cites background from "Mitochondrial Dysfunction and Bioge..."
...Mutations in proteins impairing peroxisome or mitochondrial biogenesis and/or function have been shown to lead to inherited disorders with different, and severe, phenotypic presentations [8,155]....
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TL;DR: A view is provided on the role of mitochondrial biogenesis in homeostasis of the mitochondrial mass and function, the signalling pathways beyond the induction/promotion, stimulation and inhibition of mitochondria, and the therapeutic applications aiming the repair and regeneration of defective mitochondrial biogenic (in ageing, metabolic diseases, neurodegeneration and cancer).
Abstract: In response to the energy demand triggered by developmental signals and environmental stressors, the cells launch the mitochondrial biogenesis process. This is a self-renewal route, by which new mitochondria are generated from the ones already existing. Recently, considerable progress has been made in deciphering mitochondrial biogenesis-related proteins and genes that function in health and in pathology-related circumstances. However, an outlook on the intracellular mechanisms shared by the main players that drive mitochondrial biogenesis machinery is still missing. Here, we provide such a view by focusing on the following issues: (a) the role of mitochondrial biogenesis in homeostasis of the mitochondrial mass and function, (b) the signalling pathways beyond the induction/promotion, stimulation and inhibition of mitochondrial biogenesis and (c) the therapeutic applications aiming the repair and regeneration of defective mitochondrial biogenesis (in ageing, metabolic diseases, neurodegeneration and cancer). The review is concluded by the perspectives of mitochondrial medicine and research.
218 citations
TL;DR: Using the rare premature ageing disorder Hutchinson–Gilford progeria syndrome as a paradigm, the shared mechanisms between premature ageing and ageing-associated diseases are discussed, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.
Abstract: Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson-Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.
212 citations
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TL;DR: Treatments targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria hold great promise in ageing-related neurodegenerative diseases.
Abstract: Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.
5,368 citations
"Mitochondrial Dysfunction and Bioge..." refers background in this paper
...It is hypothesized that somatic mutations of mtDNA developed during aging increase physiological decline that happens with aging and aging-related neurodegeneration [3]....
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...heterogeneity, mitochondrial contribution is probably an central common theme in these disorders [3]....
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...Many lines of evidence suggest that mitochondria can critically regulate cell death and survival, play an essential role in aging, and are one of the key features of neurodegeneration [3]....
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...There are several evidences that prove the importance of the mitochondrial dysfunction in the pathogenesis of diseases such as neurodegenerative disorders [3,11,12]....
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...Altered mitochondrial dynamics as well as mDNA mutations [8], gene mutations [9], impaired transcription contribute to mitochondrial dysfunction [10] which results in the pathogenesis of several diseases [3,11,12]....
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TL;DR: The mitochondria provide a direct link between the authors' environment and their genes and the mtDNA variants that permitted their forbears to energetically adapt to their ancestral homes are influencing their health today.
Abstract: Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the agerelated diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.
3,016 citations
"Mitochondrial Dysfunction and Bioge..." refers background in this paper
...Metabolic syndrome Reduction in mitochondrial mass [31–36] Alteration in mitochondrial morphology Decrease in fatty acid oxidation Overproduction of ROS Reduction in mitochondrial OXPHOS Neonatal fatalities Accumulation of mutations [39] Impairment of mitochondrial protein synthesis Cancer Increased accumulation of mtDNA deficiencies [40] Increased production of mitochondrial oxidative stress Increased production of mitochondrial ROS without ATP depletion Inhibition of OXPHOS by mtDNA mutations Type II diabetes Accumulation of mtDNA proteins synthesis mutations [41] Increased accumulation of mtDNA defects Downregulation of mitochondrial function and gene expression Increased production of mitochondrial ROS with ATP depletion Reduction in mitochondrial OXPHOS Neurodegenerative diseases Impairment of calcium influx [19] Dissipation of potential mitochondrial membrane Accumulation of mutant proteins in mitochondria Increased accumulation of mtDNA deficiencies Defects of Mitochondrial OXPHOS...
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...Alterations of mitochondrial activity and number are associated with age-related diseases such as cancer, diabetes, and neurodegenerative diseases [40]....
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...In addition, mitochondrial decline and mtDNA damage which play crucial roles in the etiology of cancer fall into three main classes: (1) increased accumulation of mtDNA deficiencies, (2) increased mitochondrial oxidative stress and ROS production without ATP depletion, and (3) inhibition of OXPHOS by mtDNA mutations [40]....
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TL;DR: It is demonstrated that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1.
Abstract: AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
2,649 citations
"Mitochondrial Dysfunction and Bioge..." refers background in this paper
...It is indicated that AMPK activation appears to be essential in the mitochondrial biogenesis [105] through regulating PGC-1a directly [106] or even indirectly by modulating sirtuin 1 (SIRT1) activity [101]....
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...In addition, the threonine/serine AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that is activated as a consequence of reflecting low energy reserve [101,102]....
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TL;DR: Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L).
Abstract: Mitophagy is the selective elimination of mitochondria through autophagy Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease
2,608 citations
"Mitochondrial Dysfunction and Bioge..." refers background in this paper
...This process is seen as representing a very specific pathway of QC that has significant biological relevance and performs at the organellar level [26]....
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