scholarly journals Effects of GH/IGF on the Aging Mitochondria

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1384 ◽  
Author(s):  
Sher Bahadur Poudel ◽  
Manisha Dixit ◽  
Maria Neginskaya ◽  
Karthik Nagaraj ◽  
Evgeny Pavlov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Hormone ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Cellular Aging ◽  
Mitochondrial Mass ◽  
Atp Production ◽  
And Function

The mitochondria are key organelles regulating vital processes in the eukaryote cell. A decline in mitochondrial function is one of the hallmarks of aging. Growth hormone (GH) and the insulin-like growth factor-1 (IGF-1) are somatotropic hormones that regulate cellular homeostasis and play significant roles in cell differentiation, function, and survival. In mammals, these hormones peak during puberty and decline gradually during adulthood and aging. Here, we review the evidence that GH and IGF-1 regulate mitochondrial mass and function and contribute to specific processes of cellular aging. Specifically, we discuss the contribution of GH and IGF-1 to mitochondrial biogenesis, respiration and ATP production, oxidative stress, senescence, and apoptosis. Particular emphasis was placed on how these pathways intersect during aging.

scholarly journals Growth hormone receptor controls adipogenic differentiation of chicken bone marrow mesenchymal stem cells by affecting mitochondrial function

2021 ◽  
Author(s):  
Changbin Zhao ◽  
Bowen Hu ◽  
Haohui Wei ◽  
Wen Luo ◽  
Yongxia Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Hormone ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Lipid Droplets ◽  
Growth Hormone Receptor ◽  
Adipogenic Differentiation ◽  
Expression Of Genes ◽  
And Function

Abstract Background Growth hormone receptor (GHR), a member of the type I cytokine receptor family, activates several downstream signaling pathways after binding to growth hormone (GH) to regulate cell growth and development. However, in poultry, the relations among the GHR gene, mitochondrial function, and adipocyte differentiation remain unclear. Methods In this study, we used sex-linked dwarf (SLD) chickens and normal chickens as research objects and overexpression or knockdown of GHR in bone mesenchymal stem cells (BMSCs) at the stage of adipogenic differentiation, to investigate the effects of the GHR gene on mitochondrial biogenesis, mitochondrial function and adipogenic differentiation of BMSCs. Results Yellow bone marrow in SLD chickens was higher than that in normal chickens, and lipid droplets and triglyceride content also increased in SLD bone marrow tissue. Mitochondrial biogenesis and function in BMSCs were compared between SLD and normal chickens, mitochondrial membrane potential decreased, mitochondrial ROS (mtROS) and ATP contents increased. Expression of genes associated with mitochondrial biogenesis and function, including ND1, ND2, CYTB, COX1, COX2, ATP6, ATP8, PGC1α, NRF1, and TFAM, also increased in BMSCs of SLD chickens. In addition, GHR was overexpressed and knocked down in chicken BMSCs to verify results in vitro. Overexpression of GHR increased mitochondrial membrane potential but decreased mtROS and ATP contents, oxidative phosphorylation complex enzyme activity, and mitochondrial number. Expression of genes associated with mitochondrial biogenesis and function was also repressed during adipogenic differentiation in chicken BMSCs. After overexpression of GHR, changes in adipogenic differentiation capacity of chicken BMSCs were also examined, and expression of genes associated with adipogenic differentiation, including PPARγ, C/EBPα, and C/EBPβ, decreased. Triglyceride production and number of lipid droplets (oil red O staining) also decreased after GHR overexpression. With knockdown of GHR, opposite results were observed. Conclusions GHR inhibited adipogenic differentiation of chicken BMSCs by suppressing mitochondrial function. This suppression might explain the clinical manifestation of severe fat deposition in SLD chickens.

scholarly journals GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lauren A. Callender ◽  
Johannes Schroth ◽  
Elizabeth C. Carroll ◽  
Conor Garrod-Ketchley ◽  
Lisa E. L. Romano ◽  
...  
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
T Cell ◽  
Mitochondrial Biogenesis ◽  
Cell Manipulation ◽  
Th2 Cells ◽  
Related Factor ◽  
Mitochondrial Mass ◽  
T Helper 2 ◽  
And Function

AbstractGATA3 is as a lineage-specific transcription factor that drives the differentiation of CD4+ T helper 2 (Th2) cells, but is also involved in a variety of processes such as immune regulation, proliferation and maintenance in other T cell and non-T cell lineages. Here we show a mechanism utilised by CD4+ T cells to increase mitochondrial mass in response to DNA damage through the actions of GATA3 and AMPK. Activated AMPK increases expression of PPARG coactivator 1 alpha (PPARGC1A or PGC1α protein) at the level of transcription and GATA3 at the level of translation, while DNA damage enhances expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). PGC1α, GATA3 and NRF2 complex together with the ATR to promote mitochondrial biogenesis. These findings extend the pleotropic interactions of GATA3 and highlight the potential for GATA3-targeted cell manipulation for intervention in CD4+ T cell viability and function after DNA damage.

Increased Mitochondrial Biogenesis and Function Is Necessary for Muscle Cell Differentiation

2015 ◽  
Vol 87 ◽  
pp. S131
Author(s):  
Neelu E Varghese ◽  
Gobinath Shanmugam ◽  
Daniel J Bolus ◽  
Balu K Chacko ◽  
Victor M Darley-Usmar ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Muscle Cell ◽  
Mitochondrial Biogenesis ◽  
Muscle Cell Differentiation ◽  
And Function

scholarly journals Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 136
Author(s):  
Miguel Rebollo-Hernanz ◽  
Yolanda Aguilera ◽  
Maria A. Martin-Cabrejas ◽  
Elvira Gonzalez de Gonzalez de Mejia
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Fatty Acid Synthase ◽  
Cell Model ◽  
Fibroblast Growth Factor 21 ◽  
Alcoholic Fatty Liver ◽  
Atp Production ◽  
Cocoa Shell

The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

scholarly journals A role for keratins in supporting mitochondrial organization and function in skin keratinocytes

2019 ◽  
Author(s):  
Kaylee Steen ◽  
Desu Chen ◽  
Fengrong Wang ◽  
Song Chen ◽  
Surinder Kumar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Regulation ◽  
Mouse Skin ◽  
Mitochondrial Morphology ◽  
Null Mouse ◽  
Embryonic Mouse ◽  
Atp Production ◽  
Skin Keratinocytes ◽  
Dynamics And Function ◽  
And Function

AbstractMitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.

scholarly journals Inhibition of TLR4 Signaling Affects Mitochondrial Fitness Overcoming Bortezomib Resistance in Myeloma Plasma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3073-3073
Author(s):  
Cesarina Giallongo ◽  
Daniele Tibullo ◽  
Giuseppina Camiolo ◽  
Fabrizio Puglisi ◽  
Daniela Cambria ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Mitochondrial Respiration ◽  
Research Funding ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Depolarization ◽  
Tlr4 Signaling ◽  
Mitochondrial Mass ◽  
Atp Production ◽  
Inflammatory Microenvironment

BACKGROUND Multiple myeloma (MM) is a B-cell malignancy critically dependent for survival and proliferation on signals coming from its inflammatory microenvironment in which toll-like receptors (TLR) may be potential linking elements between inflammation and cancer. It has been recently demonstrated that TLR4 pathway provides a protective effect against bortezomib (BTZ)-induced endoplasmic reticulum (ER) stress and pre-treatment of MM cells with LPS significantly reduces BTZ-induced apoptosis. AIM Since the acquisition of BTZ resistance is accompanied by an increased reliance on mitochondrial respiration, we investigated the role of TLR4 as stress-responsive mechanism that protect mitochondria during BTZ-induced ER stress as potential mechanism of drug resistance. RESULTS The activation of TLR4 signaling by LPS increased mitochondrial mass in human MM cell lines (HMCL: U266, MM1.S, OPM2, NCI-H929) and induced up-regulation of mitochondrial biogenesis markers (PGC1a, PRC and TFAM). After treatment with BTZ for 24h, all HMCL over-expressed TLR4 and its signaling was functional as suggested by up-regulation of MyD88 and MAPK activation. Compared to BTZ-sensitive cells (U266-S), U266-R showed higher levels of TLR4, p-p38 and p-ERK proteins and higher mitochondrial mass. Using a selective TLR4 inhibitor (TAK-242), we next treated U266-R cells with either 15nM BTZ, 20 μM TAK-242 or their combination. Combinatorial treatment significantly induced cell apoptosis (about 52%; p<0.001) that appeared to result from the deleterious effects of oxidative stress. Indeed, BTZ-induced intracellular ROS returned to normal levels after 3h and cells were able to up-regulate two anti-oxidant enzymes (GPX1 and GSTP1). On the contrary, TAK-242/BTZ activated a strong pro-oxidant status incresing ROS and RNS (reactive nitrogen species) levels, decreasing GSH ones and down-regulating GPX1 and GSTP1. Analyzing the effect of each treatment on mitochondrial polarization status, we observed about 6,7% of depolarized mitochondria after BTZ treatment, while TAK-242/BTZ combination induced a mitochondrial depolarization of about 69,3% (p<0.001). Moreover, cells treated with BTZ alone showed a compensatory up-regulation of the OXPHOS- (NDUFA-6 and MT-ND4) and mitochondrial fusion-related genes (mitofusin and OPA1) and TFAM. On the contrary, all these genes were down-regulated by TAK-242/BTZ combination. Also a dramatic drop in mitochondrial respiration was observed with a marked decrease in ATP production, consequent accumulation of AMP and a decreased NAD+/NADH and NADP+/NADPH ratio. Since high levels of oxidative stress and mitochondrial impairment activate mitophagy sensitizing cells to apoptosis, we evaluated co-localization of mitochondria (stained with MitoTracker) with the autophagosome marker LC3 using confocal microscopy. BTZ and TAK-242/BTZ increased Mitotracker/LC3 co-localization respectively of about 4,5 and 50 fold compared with control (BTZ vs combination: p<0.001). To evaluate whether TLR4 inhibition resensitizes resistant primary cells, CD138+ cells derived from 5 refractory/relapsed MM patients were treated with 5nM BTZ, 10mM TAK-242 or their combination. Compared to BTZ alone, combination treatment induced higher mitochondrial depolarization after 24h and significantly decreased viability of CD138+ cells after 48h. TLR4 inhibitor alone or in combination did never show cytotoxicity toward CD138- cells. CONCLUSION Taken together, these findings indicate thatTLR4 signaling is involved in the acquisition of bortezomib resistance protecting mitochondria during BTZ exposure and sustaining mitochondrial dynamics in BTZ-resitant cells. Inhibition of TLR4 may overcome bortezomib resistance in patients with relapsed/refractory MM. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Palumbo:Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria; Teva: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

2019 ◽  
Vol 57 (3) ◽  
pp. 1317-1331 ◽  
Author(s):  
Gavin Pharaoh ◽  
Daniel Owen ◽  
Alexander Yeganeh ◽  
Pavithra Premkumar ◽  
Julie Farley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Function ◽  
Spatial Learning ◽  
Mitochondrial Function ◽  
Coupling Efficiency ◽  
Redox Status ◽  
Cellular Aging ◽  
Age Related ◽  
The Brain ◽  
Circulating Levels

AbstractAge-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.

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