Mitochondrial Complex III ROS Regulate Adipocyte Differentiation

Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Cell metabolism (Impact Factor: 17.57). 10/2011; 14(4):537-44. DOI: 10.1016/j.cmet.2011.08.007
Source: PubMed


Adipocyte differentiation is characterized by an increase in mitochondrial metabolism. However, it is not known whether the increase in mitochondrial metabolism is essential for differentiation or a byproduct of the differentiation process. Here, we report that primary human mesenchymal stem cells undergoing differentiation into adipocytes display an early increase in mitochondrial metabolism, biogenesis, and reactive oxygen species (ROS) generation. This early increase in mitochondrial metabolism and ROS generation was dependent on mTORC1 signaling. Mitochondrial-targeted antioxidants inhibited adipocyte differentiation, which was rescued by the addition of exogenous hydrogen peroxide. Genetic manipulation of mitochondrial complex III revealed that ROS generated from this complex is required to initiate adipocyte differentiation. These results indicate that mitochondrial metabolism and ROS generation are not simply a consequence of differentiation but are a causal factor in promoting adipocyte differentiation.

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Available from: Robert B Hamanaka, Jan 08, 2014
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    • "Higher endogenous and uncoupled oxygen consumption is also observed after the adipogenic differentiation in hMSCs and in Simpson-Golabi-Behmel syndrome subcutaneous preadipocytes (Keuper et al., 2014; Zhang et al., 2013). Mitochondrial biogenesis is increased through adipogenic differentiation of hMSCs (Tormos et al., 2011; Zhang et al., 2013). Mitochondria of adipocytes are preferentially distributed around the lipid droplets. "
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    ABSTRACT: Adipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As a part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture, or other human activities, affect the oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, like ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. On the other hand, the environmental chemical pollutant tributyltin chloride, inhibiting the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as the obesogen hypothesis postulates.
    Disease Models and Mechanisms 09/2015; DOI:10.1242/dmm.021774 · 4.97 Impact Factor
    • "Biological events induced by metal ions have been determined to be related to an increased concentration of intracellular reactive oxygen species (ROS) because these species serve as signaling intermediates in cellular signaling pathways, including cell differentiation, proliferation and apoptosis [20] [28]. Previous studies suggested that increased intracellular ROS may play an early causal role in the terminal differentiation in keratinocytes [29] [30]. Therefore, the terminal differentiation of oral keratinocytes via increased intracellular ROS might be considered a potential biological event [31] [32]. "
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    ABSTRACT: Dental alloys containing indium (In) have been used in dental restoration for two decades; however, no study has investigated the biological effects of In ions, which may be released in the oral cavity, on human oral keratinocytes. The objective of the present study was to investigate the biological effects of In ions on human oral keratinocyte after confirming their release from a silver-palladium-gold-indium (Ag-Pd-Au-In) dental alloy. As a corrosion assay, a static immersion tests were performed by detecting the released ions in the corrosion solution from the Ag-Pd-Au-In dental alloy using inductively coupled plasma atomic emission spectroscopy. The cytotoxicity and biological effects of In ions were then studied with In compounds in three human oral keratinocyte cell lines: immortalized human oral keratinocyte (IHOK), HSC-2, and SCC-15. Higher concentrations of In and Cu ions were detected in Ag-Pd-Au-In (P<0.05) than in Ag-Pd-Au, and AgCl deposition occurred on the surface of Ag-Pd-Au-In after a 7-day corrosion test due to its low corrosion resistance. At high concentrations, In ions induced cytotoxicity; however, at low concentrations (∼0.8In(3+)mM), terminal differentiation was observed in human oral keratinocytes. Intracellular ROS was revealed to be a key component of In-induced terminal differentiation. In ions were released from dental alloys containing In, and high concentrations of In ions resulted in cytotoxicity, whereas low concentrations induced the terminal differentiation of human oral keratinocytes via increased intracellular ROS. Therefore, dental alloys containing In must be biologically evaluated for their safe use. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.
    Dental materials: official publication of the Academy of Dental Materials 12/2014; 31(2). DOI:10.1016/ · 3.77 Impact Factor
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    • "e form of hydrogen peroxide play a key role , especially in insulin signal transduction ( Loh et al . 2009 ) . Indeed , hydrogen peroxide generated by mitochondria is required for the induction of PPARγ during mesenchymal stem cell differentiation to adipocytes in vitro , an effect that is dependent on the mammalian target of rapamycin complex 1 ( Tormos et al . 2011 ) . However , higher levels of ROS , achieved through inhibition of the electron transport chain , have been associated with reduced proliferation and differentiation of 3T3 - L1 cells , 3T3 - F442A preadipocytes and human stromal vascular cells without causing cell death , thus promoting hypertrophic growth ( Carrì ere et al . 2003 , 2"
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    ABSTRACT: The role of mitochondria in white adipocytes has long been neglected due in part to their lower abundance in these cells. However, accumulating evidence suggests that mitochondria are vital for maintaining metabolic homeostasis in white adipocytes because of their involvement in adipogenesis, fatty acid (FA) synthesis and esterification, branched-chain amino acid catabolism and lipolysis. Therefore, it is not surprising that white adipose tissue function can be perturbed by altering mitochondrial components or oxidative capacity. Moreover, studies in humans and animals with significantly altered fat mass, such as in obesity or lipoatrophy, indicate that impaired mitochondrial function in adipocytes may be directly linked to the development of metabolic diseases such as diabetes and insulin resistance. However, recent studies that specifically targeted mitochondrial function in adipocytes indicated a dissociation between impaired mitochondrial oxidative capacity and systemic insulin sensitivity.This article is protected by copyright. All rights reserved
    Experimental physiology 08/2014; 99(9). DOI:10.1113/expphysiol.2014.081414 · 2.67 Impact Factor
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