scholarly journals Effect of ApoE isoforms on mitochondria in Alzheimer disease

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2404-e2411 ◽  
Author(s):  
Junxiang Yin ◽  
Eric M. Reiman ◽  
Thomas G. Beach ◽  
Geidy E. Serrano ◽  
Marwan N. Sabbagh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Human Brain ◽  
Cognitive Performance ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Dynamics ◽  
Structure And Function ◽  
Mitochondrial Structure ◽  
Apoe Isoforms ◽  
And Function

ObjectiveTo test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.MethodsWe obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).ResultsLevels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.ConclusionApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.

scholarly journals Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis

2005 ◽  
Vol 25 (14) ◽  
pp. 6225-6234 ◽  
Author(s):  
Feng Li ◽  
Yunyue Wang ◽  
Karen I. Zeller ◽  
James J. Potter ◽  
Diane R. Wonsey ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Structure And Function ◽  
Wild Type ◽  
Primary Hepatocytes ◽  
Mitochondrial Mass ◽  
Mitochondrial Structure ◽  
Direct Binding ◽  
Rat Fibroblasts ◽  
And Function

ABSTRACT Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis.

scholarly journals Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 82
Author(s):  
Veronika Kotrasová ◽  
Barbora Keresztesová ◽  
Gabriela Ondrovičová ◽  
Jacob A. Bauer ◽  
Henrieta Havalová ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Mitochondrial Protein ◽  
Structure And Function ◽  
Stress Factors ◽  
Mitochondrial Proteins ◽  
Post Translational Modification ◽  
Mitochondrial Structure ◽  
Health And Disease ◽  
And Function

The major role of mitochondria is to provide cells with energy, but no less important are their roles in responding to various stress factors and the metabolic changes and pathological processes that might occur inside and outside the cells. The post-translational modification of proteins is a fast and efficient way for cells to adapt to ever changing conditions. Phosphorylation is a post-translational modification that signals these changes and propagates these signals throughout the whole cell, but it also changes the structure, function and interaction of individual proteins. In this review, we summarize the influence of kinases, the proteins responsible for phosphorylation, on mitochondrial biogenesis under various cellular conditions. We focus on their role in keeping mitochondria fully functional in healthy cells and also on the changes in mitochondrial structure and function that occur in pathological processes arising from the phosphorylation of mitochondrial proteins.

scholarly journals Deubiquitylating enzymes in neuronal health and disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fatima Amer-Sarsour ◽  
Alina Kordonsky ◽  
Yevgeny Berdichevsky ◽  
Gali Prag ◽  
Avraham Ashkenazi
Keyword(s):  
Human Brain ◽  
Neurodegenerative Disorders ◽  
Structure And Function ◽  
Pivotal Role ◽  
Protein Homeostasis ◽  
Neuronal Function ◽  
Health And Disease ◽  
And Function

AbstractUbiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease.

scholarly journals Heterochronic Parabiosis: Old Blood Induces Changes in Mitochondrial Structure and Function of Young Mice

2020 ◽  
Author(s):  
Jenny L Gonzalez-Armenta ◽  
Ning Li ◽  
Rae-Ling Lee ◽  
Baisong Lu ◽  
Anthony J A Molina
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Structure And Function ◽  
Muscle Performance ◽  
Mitochondrial Morphology ◽  
Positive Effects ◽  
Mitochondrial Structure ◽  
And Function ◽  
Old Mice ◽  
Young Mice

Abstract Heterochronic parabiosis models have been utilized to demonstrate the role of blood-borne circulating factors in systemic effects of aging. In previous studies, heterochronic parabiosis has shown positive effects across multiple tissues in old mice. More recently, a study demonstrated old blood had a more profound negative effect on muscle performance and neurogenesis of young mice. In this study, we used heterochronic parabiosis to test the hypothesis that circulating factors mediate mitochondrial bioenergetic decline, a well-established biological hallmark of aging. We examined mitochondrial morphology, expression of mitochondrial complexes, and mitochondrial respiration from skeletal muscle of mice connected as heterochronic pairs, as well as young and old isochronic controls. Our results indicate that young heterochronic mice had significantly lower total mitochondrial content and on average had significantly smaller mitochondria compared to young isochronic controls. Expression of complex IV followed a similar pattern: young heterochronic mice had a trend for lower expression compared to young isochronic controls. Additionally, respirometric analyses indicate that young heterochronic mice had significantly lower complex I, complex I + II, and maximal mitochondrial respiration and a trend for lower complex II-driven respiration compared to young isochronic controls. Interestingly, we did not observe significant improvements in old heterochronic mice compared to old isochronic controls, demonstrating the profound deleterious effects of circulating factors from old mice on mitochondrial structure and function. We also found no significant differences between the young and old heterochronic mice, demonstrating that circulating factors can be a driver of age-related differences in mitochondrial structure and function.

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