Increased intracellular iron in mouse primary hepatocytes in vitro causes activation of the Akt pathway but decreases its response to insulin

Varghese, Joe; Vaulont, Sophie; McKie, Andrew T.; Jacob, Molly

doi:10.1016/j.bbagen.2018.05.022

Cited by 21 publications

(10 citation statements)

References 69 publications

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“…Transcriptional changes aligned with protein levels indicating that iron treatment significantly increased ferritin heavy chain and decreased TfR1 expression (Fig E). Together, these results indicate that our in vitro IO model in skeletal muscle line recapitulates the key hallmarks of IO .…”

Section: Resultssupporting

confidence: 64%

Iron overload inhibits late stage autophagic flux leading to insulin resistance

et al. 2019

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Iron overload, a common clinical occurrence, is implicated in the metabolic syndrome although the contributing pathophysiological mechanisms are not fully defined. We show that prolonged iron overload results in an autophagy defect associated with accumulation of dysfunctional autolysosomes and loss of free lysosomes in skeletal muscle. These autophagy defects contribute to impaired insulin‐stimulated glucose uptake and insulin signaling. Mechanistically, we show that iron overload leads to a decrease in Akt‐mediated repression of tuberous sclerosis complex (TSC2) and Rheb‐mediated mTORC1 activation on autolysosomes, thereby inhibiting autophagic‐lysosome regeneration. Constitutive activation of mTORC1 or iron withdrawal replenishes lysosomal pools via increased mTORC1‐UVRAG signaling, which restores insulin sensitivity. Induction of iron overload via intravenous iron‐dextran delivery in mice also results in insulin resistance accompanied by abnormal autophagosome accumulation, lysosomal loss, and decreased mTORC1‐UVRAG signaling in muscle. Collectively, our results show that chronic iron overload leads to a profound autophagy defect through mTORC1‐UVRAG inhibition and provides new mechanistic insight into metabolic syndrome‐associated insulin resistance.

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Section: Resultssupporting

confidence: 64%

Iron overload inhibits late stage autophagic flux leading to insulin resistance

et al. 2019

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“…Elevated p-AKT could also explain lower p-AMPK, as shown in the heart (Kovacic, Soltys et al, 2003, Soltys, Kovacic et al, 2006, by phosphorylation of the AMPK-α1 subunit that prevents activating phosphorylation from upstream kinases (Hawley, Ross et al, 2014). Interestingly, elevated p-AKT has been linked to increased intracellular iron (Varghese et al, 2018). Regarding elevated p-eIF2α, ER stress is a trigger, and ER stress has been documented in mitochondrial myopathy (Pereira, Tadinada et al, 2017); but ER stress was not apparent in TG hearts.…”

Section: Discussionmentioning

confidence: 99%

“…Increased levels of intracellular iron have been linked with activation of AKT (Varghese, James et al, 2018). We examined iron accumulation (ferric iron deposition) in WT and TG hearts from mice fed for 17-20 weeks on Doxy diet.…”

Section: Insights Into Upstream Regulators Of Eif2α and Mtorc1mentioning

confidence: 99%

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Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

Vásquez

Patel

Sivaramakrishnan

et al. 2020

Preprint

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Friedreich's ataxia is an inherited disorder caused by depletion of frataxin (Fxn), a mitochondrial protein involved in iron-sulfur cluster biogenesis. Cardiac dysfunction is the main cause of death; pathogenesis remains poorly understood but is expected to be linked to an energy deficit. In mice with adult-onset Fxn loss, bioenergetics analysis of heart mitochondria revealed a time-and substrate-dependent decrease in oxidative phosphorylation (oxphos). Oxphos was lower with substrates that depend on Complex I and II, but preserved for lipid substrates, especially through electron entry into Complex III via the electron transfer flavoprotein dehydrogenase. This differential substrate vulnerability is consistent with the half-lives for mitochondrial proteins.Cardiac contractility was preserved, likely due to sustained β-oxidation. Yet, a stress response was stimulated, characterized by activated mTORC1 and the p-eIF2α/ATF4 axis. This study exposes an unrecognized mechanism that maintains oxphos in the Fxn-depleted heart. The stress response that nonetheless occurs suggests energy deficit-independent pathogenesis. KEYWORDSFrataxin; bioenergetics; β-oxidation; cardiac metabolism; mitochondrial disease; integrated stress response cardiac hypertrophy (Huang et al., 2013, Seznec, Simon et al., 2004, Stram, Wagner et al., 2017, Wagner, Pride et al., 2012, which is not easily explained by elevated peIF2α and an ensuing decrease in global translation. Taken together, the mitochondrial disease literature suggests that multiple signaling pathways can be altered to potentially drive phenotypes. Thus, in any given model, it would be useful to broadly understand disrupted signaling. A broader understanding could expand the possible therapeutic targets and also reveal if disease heterogeneity needs to be considered in the context of FRDA treatments. The CKM mouse model of Fxn loss has been useful because it exhibits severe cardiac dysfunction (Huang et al., 2013, Martin, Abraham et al., 2017, Seznec et al., 2004); indeed it has been used to demonstrate the potential of gene replacement therapy in the heart (Belbellaa, Reutenauer et al., 2019, Perdomini, Belbellaa et al., 2014). Yet, this model features complete depletion of Fxn from birth and thus might reflect a developmental response. Moreover, the model has a rapid time course, making it more challenging to disentangle causes from consequences of severe pathology. A recently developed model of adult-onset Fxn depletion (Chandran, Gao et al., 2017) has several advantages for the study of the pathogenesis of cardiomyopathy in FRDA: the model avoids a developmental context, and has a wider window of time without overt major cardiac pathology. We have used this model to investigate the progression of cardiac mitochondrial metabolism and nutrient and stress signaling changes with the goal of obtaining insight into the pathogenesis of Fxn loss in the heart, specifically with regard to the impact on energy metabolism and how changes in energy metabolism might drive pathology. RESUL...

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“…At the cellular level, insulin was reported to stimulate TfR1-mediated iron uptake in primary rat adipocytes [ 93 ] and in human HepG2 hepatoma cells [ 94 ]. Importantly, excessive cellular iron accumulation has been associated with insulin resistance in primary rat adipocytes [ 95 ], primary mouse hepatocytes [ 96 ] or rat H9c2 cardiomyocytes [ 97 ]. Conversely, pharmacological iron chelation induced glucose uptake and enhanced insulin sensitivity in HepG2 cells and in the rat liver [ 53 ].…”

Section: Links Between Cellular Iron and Glucose Metabolismmentioning

confidence: 99%

Regulatory Connections between Iron and Glucose Metabolism

Fillebeen

Lam

Chow

et al. 2020

IJMS

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Iron is essential for energy metabolism, and states of iron deficiency or excess are detrimental for organisms and cells. Therefore, iron and carbohydrate metabolism are tightly regulated. Serum iron and glucose levels are subjected to hormonal regulation by hepcidin and insulin, respectively. Hepcidin is a liver-derived peptide hormone that inactivates the iron exporter ferroportin in target cells, thereby limiting iron efflux to the bloodstream. Insulin is a protein hormone secreted from pancreatic β-cells that stimulates glucose uptake and metabolism via insulin receptor signaling. There is increasing evidence that systemic, but also cellular iron and glucose metabolic pathways are interconnected. This review article presents relevant data derived primarily from mouse models and biochemical studies. In addition, it discusses iron and glucose metabolism in the context of human disease.

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Increased intracellular iron in mouse primary hepatocytes in vitro causes activation of the Akt pathway but decreases its response to insulin

Abstract: These findings may help explain why both insulin resistance and increased sensitivity have been observed in iron-overloaded states. They are of relevance to a variety of disease conditions characterized by hepatic iron overload and increased risk of diabetes.

Cited by 21 publications

References 69 publications

Iron overload inhibits late stage autophagic flux leading to insulin resistance

Iron overload inhibits late stage autophagic flux leading to insulin resistance

Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

Regulatory Connections between Iron and Glucose Metabolism

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