Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro, Márcio; Rosenstock, Tatiana R.; Oliveira, Ana M.M.; Oliveira, Catarina R.; Rego, A. Cristina

doi:10.1016/j.freeradbiomed.2014.06.023

Cited by 117 publications

(98 citation statements)

References 98 publications

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“…These results question the neuroprotective role of IGF-I in response to brain oxidative insults. However, IGF-I has shown antioxidative activity in the majority of cell types present in the mammalian brain (16 -18) and clinical benefits in brain pathologies associated with oxidative stress (17,19,20). Furthermore, our group has recently showed that IGF-I cooperates with other trophic signals produced by astrocytes, essential contributors to neuronal homeostasis (21), to protect neurons against oxidative insults (16).…”

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confidence: 99%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/ FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H 2 O 2 ), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H 2 O 2 -exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. IGF-I2 is a pleiotropic growth factor with important prosurvival effects in neurons (1). One of the main downstream targets of IGF-I is the Ser/Thr kinase AKT (2), which mediates cell survival and proliferation (3). Upon its activation, the IGF-I receptor recruits and phosphorylates IRS docking proteins (4), which allows translocation of phosphatidylinositol 3-kinase (PI3K) to the plasma membrane where it catalyzes the formation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (5). AKT is recruited to the membrane by interaction with these messengers so that it can be fully activated by PDK1 and mTORC2 kinases (3,6). This pathway is switched off (to prevent uncontrolled proliferation) through activation of the lipid and protein phosphatase PTEN, which catalyzes PIP 3 dephosphorylation (4).Cell metabolism generates potentially harmful reactive oxygen species (ROS), which at moderate levels can act as second messengers (7). However, chronic and/or abrupt increases of ROS (uncontainable by detoxification through cellular defenses) generates oxidative stress, a pathological cellular condition that can interfere with redox-sensitive signaling pathways (7). Neurons are particularly vulnerable to oxidative stress because of their low ROS detoxifying capacity (8).We previously described that oxidative stress interferes with the IGF-I/PI3K/AKT pathway by redox activation of p38 kinase to induce neuronal death (9). IGF-I signaling impairment by oxidative stress ha...

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confidence: 99%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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“…Our group has shown recently that ROS levels increase in striatal mutant cells (Ribeiro et al, 2012(Ribeiro et al, , 2014. Indeed, mutant cells showed a great capacity of oxidizing DCFH 2 to DCF (by ϳ2.3-fold, p Ͻ 0.001; Fig.…”

Section: Pdh Activation Rescues Cell Viability and Ros Production In mentioning

confidence: 72%

“…Elevated mitochondrial-derived ROS, as observed in STHdh Q111/Q111 cells (Ribeiro et al, 2013), have been implicated in the activation and stabilization of HIF-1␣, an important component of the oxygensensing pathway that has been largely described as a suppressor of metabolism and mitochondrial oxygen consumption (Papandreou et al, 2006) by directly trans-activating the genes encoding for PDK1 (Kim et al, 2006), as well as PDK2 and PDK3 Prigione et al, 2014). In striatal cells preincubated at different time points with SB (500 M), we induced hypoxia for 1 h to allow HIF-1␣ stabilization/accumulation because at normal O 2 /ROS levels, it is rapidly degraded by the proteasome (Chandel et al, 1998;Movafagh et al, 2015).…”

Section: Rescuing Of Pdh-related Mitochondrial Dysfunction By Sb Is Amentioning

confidence: 93%

“…HD is characterized by a large number of cellular abnormalities, including an increase in ROS production (Ribeiro et al, 2012(Ribeiro et al, , 2014 that may lead to protein and lipid oxidation and ultimately to a decrease in cell viability (Sorolla et al, 2010).…”

Section: Pdh Activation Rescues Cell Viability and Ros Production In mentioning

confidence: 99%

“…Among several targets, mHTT affects mitochondrial homeostasis (Gil and Rego, 2008) and disturbs gene expression by interfering with nuclear transcription (co)factors (Zhai et al, 2005;Benn et al, 2008), some linked to mitochondrial biogenesis and function (Cui et al, 2006;Cunha-Oliveira et al, 2012). mHTT also affects mitochondrial transmembrane potential (Naia et al, 2015), calcium-buffering capacity (Damiano et al, 2010), oxidative phosphorylation (Schatz, 1995;Milakovic and Johnson, 2005), and the production of reactive oxygen species (ROS) that originate in mitochondria (Ribeiro et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease

et al. 2017

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Transcriptional deregulation and changes in mitochondrial bioenergetics, including pyruvate dehydrogenase (PDH) dysfunction, have been described in Huntington's disease (HD). We showed previously that the histone deacetylase inhibitors (HDACIs) trichostatin A and sodium butyrate (SB) ameliorate mitochondrial function in cells expressing mutant huntingtin. In this work, we investigated the effect of HDACIs on the regulation of PDH activity in striatal cells derived from HD knock-in mice and YAC128 mice. Mutant cells exhibited decreased PDH activity and increased PDH E1alpha phosphorylation/inactivation, accompanied by enhanced protein levels of PDH kinases 1 and 3 (PDK1 and PDK3). Exposure to dichloroacetate, an inhibitor of PDKs, increased mitochondrial respiration and decreased production of reactive oxygen species in mutant cells, emphasizing PDH as an interesting therapeutic target in HD. Treatment with SB and sodium phenylbutyrate, another HDACI, recovered cell viability and overall mitochondrial metabolism in mutant cells. Exposure to SB also suppressed hypoxia-inducible factor-1 (HIF-1␣) stabilization and decreased the transcription of the two most abundant PDK isoforms, PDK2 and PDK3, culminating in increased PDH activation in mutant cells. Concordantly, PDK3 knockdown improved mitochondrial function, emphasizing the role of PDK3 inactivation on the positive effects achieved by SB treatment. YAC128 mouse brain presented higher mRNA levels of PDK1-3 and PDH phosphorylation and decreased energy levels that were significantly ameliorated after SB treatment. Furthermore, enhanced motor learning and coordination were observed in SB-treated YAC128 mice. These results suggest that HDACIs, particularly SB, promote the activity of PDH in the HD brain, helping to counteract HD-related deficits in mitochondrial bioenergetics and motor function.

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TREM2‐IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke

Yang,

Qin,

Chen

et al. 2023

Advanced Science

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Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single‐nuclei RNA sequencing, a microglial subcluster up‐regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down‐stream molecules of Trem2, and Trem2‐Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2‐Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

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Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Cited by 117 publications

References 98 publications

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease

TREM2‐IGF1 Mediated Glucometabolic Enhancement Underlies Microglial Neuroprotective Properties During Ischemic Stroke

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