title: Mitochondrial dysfunction in the hypertensive rat brain: respiratory complexes exhibit assembly defects in hypertension.
abstract: The central nervous system plays a critical role in the normal control of arterial blood pressure and in its elevation in virtually all forms of hypertension. Mitochondrial dysfunction has been increasingly associated with the development of hypertension. Therefore, we examined whether mitochondrial dysfunction occurs in the brain in hypertension and characterized it at the molecular scale. Mitochondria from whole brain and brain stem from 12-week-old spontaneously hypertensive rats with elevated blood pressure (190+/-5 mm Hg) were compared against those from age-matched normotensive (134+/-7 mm Hg) Wistar Kyoto rats (n=4 in each group). Global differential analysis using 2D electrophoresis followed by tandem mass spectrometry-based protein identification suggested a downregulation of enzymes involved in cellular energetics in hypertension. Targeted differential analysis of mitochondrial respiratory complexes using the classical blue-native SDS-PAGE/Western method and a complementary combination of sucrose-gradient ultracentrifugation/tandem mass spectrometry revealed previously unknown assembly defects in complexes I, III, IV, and V in hypertension. Interestingly, targeted examination of the brain stem, a regulator of cardiovascular homeostasis and systemic blood pressure, further showed the occurrence of mitochondrial complex I dysfunction, elevated reactive oxygen species production, decreased ATP synthesis, and impaired respiration in hypertension. Our findings suggest that in already-hypertensive spontaneously hypertensive rats, the brain respiratory complexes exhibit previously unknown assembly defects. These defects impair the function of the mitochondrial respiratory chain. This mitochondrial dysfunction localizes to the brain stem and is, therefore, likely to contribute to the development, as well as to pathophysiological complications, of hypertension.
authors.affiliation: Department of Biochemistry, Institute for Biomolecular Design, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ana
authors.initials: A
authors.lastname: Lopez-Campistrous
authors.forename: Li
authors.initials: L
authors.lastname: Hao
authors.forename: Wang
authors.initials: W
authors.lastname: Xiang
authors.forename: Dong
authors.initials: D
authors.lastname: Ton
authors.forename: Paul
authors.initials: P
authors.lastname: Semchuk
authors.forename: Joerg
authors.initials: J
authors.lastname: Sander
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ellison
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Patron
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D002319:Cardiovascular System / Q000503:physiopathology; D004318:Doxycycline / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis; D006973:Hypertension / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000209:etiology*; D009097:Multienzyme Complexes / Q000187:drug effects / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D053719:Tandem Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D008666:Metalloendopeptidases; D004318:Doxycycline