Impaired Mitochondrial Metabolism and Mammary Carcinogenesis
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Impaired Mitochondrial Metabolism and Mammary Carcinogenesis Nagendra Yadava & Sallie S. Schneider & D. Joseph Jerry & Chul Kim
Received: 1 October 2012 / Accepted: 13 December 2012 / Published online: 27 December 2012 # Springer Science+Business Media New York 2012
Abstract Mitochondrial oxidative metabolism plays a key role in meeting energetic demands of cells by oxidative phosphorylation (OxPhos). Here, we have briefly discussed (a) the dynamic relationship that exists among glycolysis, the tricarboxylic acid (TCA) cycle, and OxPhos; (b) the evidence of impaired OxPhos (i.e. mitochondrial dysfunction) in breast cancer; (c) the mechanisms by which mitochondrial dysfunction can predispose to cancer; and (d) the effects of host and environmental factors that can negatively affect mitochondrial function. We propose that impaired OxPhos could increase susceptibility to breast cancer via suppression of the p53 pathway, which plays a critical role in preventing tumorigenesis. OxPhos is sensitive to a large number of factors intrinsic to the host (e.g. inflammation) as well as environmental exposures (e.g. pesticides, herbicides and other compounds). Polymorphisms in over 143 genes can also influence the OxPhos system. Therefore, declining mitochondrial oxidative metabolism with age due to host and environmental exposures could be a common mechanism predisposing to cancer.
N. Yadava : S. S. Schneider : D. J. Jerry : C. Kim Pioneer Valley Life Sciences Institute, Springfield, MA 01107, USA N. Yadava (*) Division of Endocrinology, Diabetes & Metabolism at Baystate Medical Center of Tufts University School of Medicine, Springfield, MA 01199, USA e-mail: [email protected] N. Yadava Department of Biology, University of Massachusetts, Amherst, MA 01003, USA S. S. Schneider : D. J. Jerry Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA
Keywords Mitochondrial metabolism . Oxidative phosphorylation . OxPhos . Inflammation . Tumor suppressor p53 . Breast cancer Abbreviations NAD+ and NADH NADP+ and NADPH ADP ATP Pi FAD and FADH2 nDNA mtDNA OxPhos TCA CoA
Oxidized and reduced nicotinamide adenine dinucleotides, respectively Phosphorylated forms of NAD+ and NADH, respectively Adenosine diphosphate Adenosine triphosphate Inorganic phosphate Oxidized and reduced flavin adenine dinucleotides, respectively Nuclear-DNA Mitochondrial-DNA Oxidative phosphorylation Tricarboxylic acid Coenzyme A
Introduction Metabolism is central to cellular physiology. It provides energy in the form of adenosine 5′-triphosphate (ATP) and building blocks (other nucleotides, lipids, amino acids, etc.) for different cellular processes including cell growth, proliferation and supporting functions of differentiated cells such as milk synthesis in lactating mammary glands [1, 2]. The overall cellular metabolism relies on glycolysis, the tricarboxylic acid (TCA, also known as citric acid or Krebs) cycle, and oxidative phosphorylation (OxPhos). The reactions of glycolysis, the TCA cycle and OxPho
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