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Review
. 2020 Jun 2;9(6):1384.
doi: 10.3390/cells9061384.

Effects of GH/IGF on the Aging Mitochondria

Affiliations
Review

Effects of GH/IGF on the Aging Mitochondria

Sher Bahadur Poudel et al. Cells. .

Abstract

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.

Keywords: aging; growth hormone; insulin-like growth factor-1; mitochondria; oxidative stress; senescence.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic summary of the major molecules composing the somatotropic axis. GHRH—Growth hormone-releasing hormone, SST—Somatostatin, GH—Growth hormone, GHR—Growth hormone receptor, IGF—Insulin-like growth factor, IGFBP—Insulin-like growth factor binding protein, IGF-IR—insulin like growth factor receptor-1, IR—Insulin receptor, ALS—Acid labile subunit, PAPPA2—Pregnancy-associated plasma protein-A2.
Figure 2
Figure 2
Schematic summary of the major effects of GH/IGF-1 on mitochondrial gene expression: Upon binding of GH to the GHR, the Janus kinase (JAK)-Signal transducer and activator of transcription 5 (STAT5) signaling pathway is activated, leading mostly to increases in IGF-1 transcription. Binding of IGF-1 to the tyrosine kinase IGF-1R stimulates several signaling pathways including the Phosphoinositide-3-kinase (PI3K)/Protein kinase B (PKB or AKT) and Ras/Raf/Mitogen-activated protein kinase (MAPK), involving phosphorylation and dephosphorylation of candidate proteins. This cascade leads to transcriptional activity of genes involved in mitochondrial biogenesis, control of Reactive oxygen species (ROS), cell survival (antiapoptotic), and genes involved in metabolism.
Figure 3
Figure 3
Mitochondria produce ATP and reactive oxygen species (ROS) as byproducts of oxidative phosphorylation (OXPHOS): In youth, ROSs are neutralized by the antioxidant system. Accumulation of proteins and enzymes damaged by escaped ROS leads to impairment of mitochondrial function during aging. Mitochondrial dysfunction is correlated with the decline in GH/IGF1 signaling and is linked to a variety of age-related diseases.
Figure 4
Figure 4
Effect of oxidative stress on thioredoxin-interacting protein (TXNIP) levels [79]: (A) Effect of oxidative stress on TXNIP levels in Laron syndrome (LS)-derived and control lymphoblastoids. Four individual LS and three control lymphoblastoid cell lines were treated with 300 mM of H2O2 for 2 h, and levels of TXNIP mRNA were measured by RT-QPCR. A value of 1 was given to TXNIP mRNA levels in untreated cells (solid bars). (B) Serum-starved HEK293 cells were treated with H2O2 (100 mM) or IGF1 (50 ng/mL) or both for 2 h. TXNIP and tubulin were detected by Western blotting.
Figure 5
Figure 5
Effect of glucose stress on TXNIP levels [79]: (A) Serum-starved 3T3-L1 cells were maintained in medium with different concentrations of glucose in the presence or absence of IGF1 or insulin for 6 h. TXNIP, phospho-IGF-1R, and tubulin were detected by Western blotting. Schematic representation of the regulation of TXNIP by IGF1 signaling: (B) Under normal serum-free conditions, TXNIP is upregulated upon oxidative and glucose stresses. The activated TXNIP inhibits glucose uptake and is capable of mediating mitochondrial mediated apoptosis. (C) Upon IGF1 stimulation, TXNIP is downregulated even under oxidative and glucose stresses. Suppression of TXNIP leads to inhibition of apoptosis with ensuing increase in cell proliferation.
Figure 6
Figure 6
The effects of IGF-1 on mitochondria-mediated apoptosis: Cellular stress leads to permeability transition pore (PTP) opening, reduction in OXPHOS function, membrane potential, and ATP production, while ROS production is increased, altogether leading to cyt c release. Cytosolic Cyt c activates the apoptosome, leading to cell death. IGF-1R-mediated inhibition of apoptosis occurs via activation of two major signaling pathways that trigger phosphorylation cascade of cytosolic and nuclear proteins regulating transcription and activation of proteins involved in protection from apoptosis. The AKT pathway leads to phosphorylation of Forkhead box transcription factors of the class O (FOXO) proteins and subsequent inhibition of their transcriptional activity. The MAPK pathway, stimulated by IGF-1 binding, activates the Bcl antiapoptotic family of proteins.

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