The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases

Breuer, Megan E.; Koopman, Werner J.H.; Koene, Saskia; Nooteboom, Marco; Rodenburg, Richard J.; Willems, Peter H.G.M.; Smeitink, Jan A.M.

doi:10.1016/j.nbd.2012.03.007

Cited by 75 publications

(56 citation statements)

References 73 publications

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“…Mitochondrial dysfunction is seen in a number of neurodegenerative conditions including AD, Leber’s hereditary optic neuropathy(LHON), Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) [78], Mitochondria may account for observed relationships between advancing age and an age-related increase in the incidence of various neurodegenerative diseases, as mitochondrial function declines with advancing age [79], In various tissues, including the nervous system, somatic mutations accumulate within mitochondrial DNA (mtDNA), which may contribute to or compound age-related changes in mitochondrial function [80,81], Some have proposed declines in mitochondrial function that exceed a threshold can contribute to the onset or progression of neurodegenerative diseases [82,83], According to one scheme, an individual’s genetic inheritance helps to define a baseline level of mitochondrial function, and the rate at which that individual’s mitochondria decline over decades further determines how rapidly the individual approaches a functional threshold that allows for the manifestation of an age related disease such as AD [84]. …”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

Menta

Swerdlow

2018

Neurochem Res

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Alzheimer's disease (AD) is a neurodegenerative disease that devastates the lives of its victims, and challenges the family members and health care infrastructures that care for them. Clinically, attempts to understand AD have focused on trying to predict the presence of, and more recently demonstrate the presence of, its characteristic amyloid plaque and neurofibrillary tangle pathologies. Fundamental research has also traditionally focused on understanding the generation, content, and pathogenicity of plaques and tangles, but in addition to this there is now an emerging independent interest in other molecular phenomena including apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial function. While studies emphasizing the role of these phenomena have provided valuable AD insights, it is interesting that at the molecular level these entities extensively intertwine and interact. In this review, we provide a brief overview of why apolipoprotein E, lipid metabolism, neuroinflammation, and mitochondrial research have become increasingly ascendant in the AD research field, and present the case for studying these phenomena from an integrated perspective.

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Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

Menta

Swerdlow

2018

Neurochem Res

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“…Mitochondria produce significant amounts of ATP through the oxidation of carbohydrates, fats and amino acids, a process known as oxidative phosphorylation [84]. The mechanism underlying this coupling of fuel oxidation to the mitochondrial ATP synthesis was first demonstrated by the Peter Mitchell's chemiosmotic theory [85,86].…”

Section: Mitochondrial Oxidative Phosphorylationmentioning

confidence: 99%

Hyperglycemia, Hypoglycemia and Dementia: Role of Mitochondria and Uncoupling Proteins

Cardoso¹,

Correia²,

Santos³

et al. 2013

CMM

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Diabetes mellitus is one of the most prevalent chronic diseases. Since glucose is the main fuel of the brain, its levels should be maintained within a narrow range to ensure normal brain function. Indeed, the literature shows that uncontrolled blood glucose levels, whether too high or too low, impact brain structure and function potentiating cognitive impairment. Uncoupling proteins (UCPs) are a family of mitochondrial anion carrier proteins located on the inner mitochondrial membrane, and their primary function is to leak protons from the intermembrane space into the mitochondrial matrix. The specific role of neuronal UCPs has been widely discussed and although there is no general agreement, there is a strong conviction that these proteins may be involved in the defense against mitochondrial reactive oxygen species (ROS) production and, consequently, protecting against oxidative damage. The generation of ROS is increasingly recognized as playing an important role in diabetes, neurodegenerative disorders and aging where mitochondria are both sources and targets of these reactive species. This review examines the neurodegenerative events associated with diabetes, highlighting the role of hyperglycemia and/or hypoglycemia on cognitive function. The role of mitochondria, neuronal UCPs and their impact in central nervous system will be elucidated. Finally, we will discuss neuronal UCPs as possible therapeutic targets for the treatment of diabetes-associated central complications and neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases.

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“…Sufficient energy levels must be maintained for cells to thrive (Wallace, 2011), and it is clear that dysregulated bioenergetics plays an important role in many diseases (Raimundo, 2014). In cancer, energy production is increased to support rapid proliferation (Formentini et al, 2010; Vander Heiden et al, 2009; Vander Heiden et al, 2012); while in many neurodegenerative diseases, core energy producing pathways are compromised leading to impaired cellular function and decreased viability (Breuer et al, 2013; Federico et al, 2012; Xun et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels

et al. 2014

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Summary Altered cellular bioenergetics and mitochondrial function are major features of several diseases including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions to examine their effect on cellular ATP levels. We identified a mechanism by which electron transport chain perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux; thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels, AMPK signaling, and whose expression significantly correlates with glioma patient survival. As a result, this study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.

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The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases

Cited by 75 publications

References 73 publications

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

Hyperglycemia, Hypoglycemia and Dementia: Role of Mitochondria and Uncoupling Proteins

A Mitochondrial RNAi Screen Defines Cellular Bioenergetic Determinants and Identifies an Adenylate Kinase as a Key Regulator of ATP Levels

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