title: Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase.
abstract: Mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is associated with severe hypoglycemia, cardiac dysfunction, and sudden death in neonates and children. Sudden death is common, but the underlying mechanisms are not fully understood. We report on a mouse model of VLCAD deficiency with a phenotype induced by the stresses of fasting and cold, which includes hypoglycemia, hypothermia, and severe bradycardia. The administration of glucose did not rescue the mice under stress conditions, but rewarming alone consistently led to heart rate recovery. Brown adipose tissue (BAT) from the VLCAD-/- mice showed elevated levels of the uncoupling protein isoforms and peroxisome proliferator-activated receptor-alpha. Biochemical assessment of the VLCAD(/- mice BAT showed increased oxygen consumption, attributed to uncoupled respiration in the absence of stress. ADP-stimulated respiration was 23.05 (SD 4.17) and 68.24 (SD 6.3) nmol O2.min(-1).mg mitochondrial protein(-1) for VLCAD+/+ and VLCAD-/- mice, respectively (P < 0.001), and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated respiration was 35.9 (SD 3.6) and 49.3 (SD 9) nmol O2.min(-1).mg mitochondrial protein(-1) for VLCAD+/+ and VLCAD-/- mice, respectively (P < 0.20), but these rates were insufficient to protect them in the cold. We conclude that disturbed mitochondrial bioenergetics in BAT is a critical contributing factor for the cold sensitivity in VLCAD deficiency. Our observations provide insights into the possible mechanisms of stress-induced death in human newborns with abnormal fat metabolism and elucidate targeting of specific substrates for particular metabolic needs.
authors.affiliation: Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-9119, USA. vernat.exil@vanderbilt.edu
authors.forename: Vernat J
authors.initials: VJ
authors.lastname: Exil
authors.forename: Carla D
authors.initials: CD
authors.lastname: Gardner
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Rottman
authors.forename: Harold
authors.initials: H
authors.lastname: Sims
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Bartelds
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.forename: Rekha
authors.initials: R
authors.lastname: Sindhal
authors.forename: Gemin
authors.initials: G
authors.lastname: Ni
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001919:Bradycardia / Q000150:complications / Q000503:physiopathology*; D004734:Energy Metabolism; D006339:Heart Rate; D007003:Hypoglycemia / Q000150:complications* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000150:complications / Q000503:physiopathology*; D013577:Syndrome
chemical_list: D001786:Blood Glucose; D044942:Acyl-CoA Dehydrogenase, Long-Chain