Camacho-Pereira 2013 Abstract IOC75

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Camacho-Pereira J (2013) CD38 as a regulator of mitochondrial function. Mitochondr Physiol Network 18.03.

Link: IOC75 Open Access

Camacho-Pereira J, Matalonga J, Escandes C, Chini EN (2013)

Event: IOC75

Nicotinamide adenine dinucleotide (NAD) is a key metabolite involved in many cellular signaling in different metabolic conditions. NAD, as a cofactor of key enzymes in glycolisis, tricarboxilic acid cycle and oxidative phosphorylation, is important to cell energy generation, but also NAD is a substrate for generation of second messengers such as cyclic-ADP-ribose (cADPR) and has a role as a substrate and regulator of the NAD dependent deacetylases sirtuins (SIRTs). Lately, many studies have been demonstrating that regulating NAD levels can be used as therapy for many conditions as aging, high caloric diet, diabetes and other metabolic diseases, but further investigations are required to elucidate how the steady state of NAD regulates various aspects of mitochondrial function [1]. CD38 is a surface enzyme involved in different mechanism as calcium signaling, cell adhesion and signal transduction. In our scenario, CD 38 emerges as the main NADase in mammalian cells, and a regulator of intracellular NAD levels [2]. Our group demonstrated that CD38-deficient mice (CD38-/-) are protected against high-fat diet-induced obesity indicating that CD38-/- animals have a higher metabolic rate compared to wild-type mice (WT) [3]. As a regulator of NAD levels, CD38 can be a potential target for the regulation of mitochondrial function derived by NAD metabolism. We were able to demonstrate that the oxygen consumption in mitochondria isolated from CD38-/- mice is 2.5 times higher compared to the WT. To further confirm the regulation of mitochondria function promoted by CD38, we over expressed the CD38 vector in HEK 293T cells, which constitutively does not express this protein. Intact cells over expressing CD38 have 25% less oxygen consumption than the control vector. The decrease in respiration levels is mostly observed in maximum electron transport capacity (ETC). With the increase in CD38 expression, NAD levels in HEK293T decreases by 80%. The mitochondrial number is apparently increased in CD38 transfected cells but an abnormally mitochondria shape is observed by electron microscope. Other process that involves decrease in mitochondria respiration is immune response. Macrophages isolated from WT mice treated with 50ng/ml of LPS increased CD38 expression which was followed by a decreased in oxygen consumption, mostly in basal and ETC respiration. When this experiment was performed in macrophages isolated from CD38-/- animals, the decrease in oxygen consumption was abolished, confirming that CD38 could be an important key in the regulation of mitochondria respiration by LPS.

  1. Stein LR, Imai S (2012) The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab 23: 420-428.
  2. Chini EN (2009) CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr Pharm Des 15: 57-63.
  3. Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN (2007) The enzyme CD38 (a NAD glycohydrolase, EC is necessary for the development of diet-induced obesity. FASEB J 21: 3629-3639.

Keywords: NAD metabolism, CD38, Mitochondrial Function

O2k-Network Lab: US MN Rochester Chini EN

Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Aging;senescence, Obesity 

Organism: Mouse  Tissue;cell: Liver, HEK, Macrophage-derived  Preparation: Intact cells, Permeabilized cells, Isolated mitochondria 

Regulation: Inhibitor  Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 

Affiliations and author contributions

Laboratory of Signal Transduction, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905