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Aging mitochondria

Xiyan Li, Xin Wang, Michael P Snyder
Metformin elicits pleiotropic effects that are beneficial for treating diabetes, and as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30-50%; the heme-targeting drug artemisinin operates at a greater potency...
December 15, 2018: G3: Genes—Genomes—Genetics
Adam R Konopka, Jaime L Laurin, Hayden M Schoenberg, Justin J Reid, William M Castor, Christopher A Wolff, Robert V Musci, Oscar D Safairad, Melissa A Linden, Laurie M Biela, Susan M Bailey, Karyn L Hamilton, Benjamin F Miller
Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years)...
December 11, 2018: Aging Cell
Carolyn J Vivian, Travis M Hagedorn, Roy A Jensen, Amanda E Brinker, Danny R Welch
Many inbred strains of mice develop spontaneous tumors as they age. Recent awareness of the impacts of mitochondrial DNA (mtDNA) on cancer and aging has inspired developing a mitochondrial-nuclear exchange (MNX) mouse model in which nuclear DNA is paired with mitochondrial genomes from other strains of mouse. MNX mice exhibit mtDNA influences on tumorigenicity and metastasis upon mating with transgenic mice. However, we also wanted to investigate spontaneous tumor phenotypes as MNX mice age. Utilizing FVB/NJ, C57BL/6J, C3H/HeN, and BALB/cJ wild-type inbred strains, previously documented phenotypes were observed as expected in MNX mice with the same nuclear background...
December 14, 2018: Cancer Metastasis Reviews
Jyung Mean Son, Changhan Lee
Aging is accompanied by a time-dependent progressive deterioration of multiple factors of the cellular system. The past several decades have witnessed major leaps in our understanding of the biological mechanism of aging using dietary, genetic, pharmacological, and physical interventions. Metabolic processes, including nutrient sensing pathways and mitochondrial function, have emerged as prominent regulators of aging. Mitochondria have been considered to play a key role largely due to their production of reactive oxygen species (ROS), resulting in DNA damage that accumulates over time and ultimately causes cellular failure...
December 14, 2018: BMB Reports
Ashraf S Gorgey, Oksana Witt, Laura O'Brien, Christopher Cardozo, Qun Chen, Edward J Lesnefsky, Zachary A Graham
Mitochondria are responsible for aerobic respiration and large-scale ATP production in almost all cells of the body. Their function is decreased in many neurodegenerative and cardiovascular disease states, in metabolic disorders such as type II diabetes and obesity, and as a normal component of aging. Disuse of skeletal muscle from immobilization or unloading triggers alterations of mitochondrial density and activity. Resultant mitochondrial dysfunction after paralysis, which precedes muscle atrophy, may augment subsequent release of reactive oxygen species leading to protein ubiquitination and degradation...
December 11, 2018: European Journal of Applied Physiology
Ruoxi Wang, Jieqiong Tan, Tingting Chen, Hailong Han, Runyi Tian, Ya Tan, Yiming Wu, Jingyi Cui, Fang Chen, Jie Li, Lu Lv, Xinjie Guan, Shuai Shang, Jiahong Lu, Zhuohua Zhang
Mutations in ATP13A2 cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson's disease (PD). Recent work tied ATP13A2 to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment. ATP13A2 deficiency impaired autophagosome-lysosome fusion in cultured cells and in in vitro reconstitution assays...
December 11, 2018: Journal of Cell Biology
Vikas Kumar, T R Santhosh Kumar, C C Kartha
Mitochondrial dysfunction is widely recognized as a major factor for the progression of cardiac failure. Mitochondrial uptake of metabolic substrates and their utilization for ATP synthesis, electron transport chain activity, reactive oxygen species levels, ion homeostasis, mitochondrial biogenesis, and dynamics as well as levels of reactive oxygen species in the mitochondria are key factors which regulate mitochondrial function in the normal heart. Alterations in these functions contribute to adverse outcomes in heart failure...
December 10, 2018: Heart Failure Reviews
Baishali Alok Jana, Pavan Kumar Chintamaneni, Praveen Thaggikuppe Krishnamurthy, Ashish Wadhwani, Suresh Kumar Mohankumar
Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis...
December 8, 2018: Molecular Biology Reports
María Gómez-Serrano, Emilio Camafeita, Marta Loureiro, Belén Peral
Mitochondria are highly dynamic and regulated organelles that historically have been defined based on their crucial role in cell metabolism. However, they are implicated in a variety of other important functions, making mitochondrial dysfunction an important axis in several pathological contexts. Despite that conventional biochemical and molecular biology approaches have provided significant insight into mitochondrial functionality, innovative techniques that provide a global view of the mitochondrion are still necessary...
2018: Oxidative Medicine and Cellular Longevity
Zhuping Jin, Limin Sun, Guangdong Yang, Yanxi Pei
Hydrogen sulfide (H2 S) is a novel gasotransmitter in both mammals and plants. H2 S plays important roles in various plant developmental processes and stress responses. Leaf senescence is the last developmental stage and is a sequential degradation process that eventually leads to leaf death. A mutation of the H2 S-producing enzyme-encoding gene L-cysteine desulfhydrase1 ( DES1 ) leads to premature leaf senescence but the underlying mechanisms are not clear. In this present study, wild-type, DES1 defective mutant ( des1 ) and over-expression ( OE-DES1 ) Arabidopsis plants were used to investigate the underlying mechanism of H2 S signaling in energy production and leaf senescence under drought stress...
2018: Frontiers in Plant Science
Noga Ron-Harel, Giulia Notarangelo, Jonathan M Ghergurovich, Joao A Paulo, Peter T Sage, Daniel Santos, F Kyle Satterstrom, Steven P Gygi, Joshua D Rabinowitz, Arlene H Sharpe, Marcia C Haigis
T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity...
December 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jean-Claude Farré, Shanmuga S Mahalingam, Marco Proietto, Suresh Subramani
Peroxisomes are conserved organelles of eukaryotic cells with important roles in cellular metabolism, human health, redox homeostasis, as well as intracellular metabolite transfer and signaling. We review here the current status of the different co-existing modes of biogenesis of peroxisomal membrane proteins demonstrating the fascinating adaptability in their targeting and sorting pathways. While earlier studies focused on peroxisomes as autonomous organelles, the necessity of the ER and potentially even mitochondria as sources of peroxisomal membrane proteins and lipids has come to light in recent years...
December 10, 2018: EMBO Reports
Michaela Keuper, Lucia Berti, Bernhard Raedle, Stephan Sachs, Anja Böhm, Louise Fritsche, Andreas Fritsche, Hans-Ulrich Häring, Martin Hrabě de Angelis, Martin Jastroch, Susanna M Hofmann, Harald Staiger
BACKGROUND/OBJECTIVES: Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist...
November 26, 2018: Molecular Metabolism
Xian Xie, Yi Gao, Min Zeng, Yi Wang, Tao-Feng Wei, Yun-Bi Lu, Wei-Ping Zhang
Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer's disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests...
December 6, 2018: Metabolic Brain Disease
Jingjing Cai, He Zhang, Yun-Feng Zhang, Zhonglou Zhou, Shengzhou Wu
Retinal pigment epithelial cells (RPEs), a pigmented cell layer in the outer retina, are constantly exposed to photo-oxidative stress. Autophagy relieves the stress by removing oxidative protein adducts, protein aggregates, and damaged mitochondria. We previously found that miR-29 is downregulated in choroid/RPE tissue in a model of exudative age-related macular degeneration (AMD), suggesting that miR-29 deficiency may contribute to autophagy inhibition and AMD progression. Here we wanted to test whether overexpression of miR-29 in RPEs could enhance autophagy, thereby facilitating removal of drusen components...
December 1, 2018: Experimental Cell Research
Lianteng Zhi, Qi Qin, Tanziyah Muqeem, Erin L Seifert, Wencheng Liu, Sushuang Zheng, Chenjian Li, Hui Zhang
Mutations and deletions in PTEN-induced kinase 1 (PINK1) cause autosomal recessive Parkinson's disease (PD), the second most common neurodegenerative disorder. PINK1 is a nuclear-genome encoded Ser/Thr kinase in mitochondria. PINK1 deletion was reported to affect dopamine (DA) levels in the striatum and mitochondrial functions but with conflicting results. The role of PINK1 in mitochondrial function and in PD pathogenesis remains to be elucidated thoroughly. In this study, we measured DA release using fast-scan cyclic voltammetry in acute striatal slices from both PINK1 knockout (KO) and wild-type (WT) mice at different ages...
November 2, 2018: Neurobiology of Aging
Tânia R Soares, Sara D Reis, Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the huntingtin protein. Expansions above 40 polyglutamine repeats are invariably fatal, following a symptomatic period characterised by choreiform movements, behavioural abnormalities, and cognitive decline. While mutant huntingtin (mHtt) is widely expressed from early life, most patients with HD present in mid-adulthood, highlighting the role of ageing in disease pathogenesis. mHtt undergoes proteolytic cleavage, misfolding, accumulation, and aggregation into inclusion bodies...
November 28, 2018: Ageing Research Reviews
Hernán H Dieguez, Horacio E Romeo, Agustina Alaimo, María F González Fleitas, Marcos L Aranda, Ruth E Rosenstein, Damián Dorfman
Non-exudative age-related macular degeneration (NE-AMD) represents the leading cause of blindness in the elderly. The macular retinal pigment epithelium (RPE) lies in a high oxidative environment because its high metabolic demand, mitochondria concentration, reactive oxygen species levels, and macular blood flow. It has been suggested that oxidative stress-induced damage to the RPE plays a key role in NE-AMD pathogenesis. The fact that the disease limits to the macular region raises the question as to why this area is particularly susceptible...
November 28, 2018: Free Radical Biology & Medicine
Nathalie Arnal, Gustavo Morel, Carlos A Marra, Mariana Astiz
Dimethoate (DMT), a widely used Organophosphorous insecticide, was administered for 5 weeks (sub-chronic) at low dose (15 mg/kg b.w.) to male Wistar rats with the aim to simulate potential exposure to pesticide residues in food and water. The induction of cell death programs was investigated in two brain regions, cortex (Cx) and substantia nigra (SN), after the exposure period. We found that DMT increased cytochrome C (CytC) release from mitochondria, the Bax/Bcl-2 ratio, the activity of caspase-3 and calpains, in both brain regions compared to VEH injected ones...
November 28, 2018: Toxicology and Applied Pharmacology
Blanca Hernando-Rodríguez, Marta Artal-Sanz
Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress, and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the oxidative phosphorylation (OXPHOS) system for ATP production. It requires, in addition, the import of a large number of proteins from the cytosol to keep optimal mitochondrial function and metabolism...
November 29, 2018: Cells
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