title: Substrate modulation of fatty acid effects on energization and respiration of kidney proximal tubules during hypoxia/reoxygenation.
abstract: Kidney proximal tubules subjected to hypoxia/reoxygenation develop a nonesterified fatty acid-induced energetic deficit characterized by persistent partial mitochondrial deenergization that can be prevented and reversed by citric acid cycle substrates. To further assess the role of competition between fatty acids and substrates on inner membrane substrate carriers in the deenergization and the contribution to deenergization of fatty acid effects on respiratory function, digitonin-permeabilized rabbit and mouse tubules were studied using either addition of exogenous oleate after control normoxic incubation or increases of endogenous fatty acids produced by hypoxia/reoxygenation. The results demonstrated major effects of matrix oxaloacetate accumulation on succinate-supported energization and respiration and their modification by fatty acids. Improvements of energization in the presence of fatty acids by glutamate were shown to result predominantly from lowering matrix oxaloacetate rather than from amelioration of transmembrane cycling of fatty acids and uncoupling. Mouse tubules had 2.5 fold higher rates of succinate utilization, which resulted in stronger effects of oxaloacetate accumulation than rabbit tubules. Hypoxia/reoxygenation induced respiratory inhibition that was more severe for complex I-dependent substrates. Fatty acids themselves did not acutely contribute to this respiratory inhibition, but lowering them during 60 min. reoxygenation to allow recovery of ATP during that period alleviated it. These data clarify the basis for the nonesterified fatty acid-induced mitochondrial energetic deficit in kidney proximal tubules that impairs structural and functional recovery and provide insight into interactions that need to be considered in the design of substrate-based interventions to improve mitochondrial function.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, United States of America; Division of Nephrology, Department of Internal Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bienholz
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Taweel
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Roeser
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kribben
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, United States of America; Division of Nephrology, Department of Internal Medicine, University Duisburg-Essen, Essen, Germany; Division of Nephrology and Hypertension, Department of Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Feldkamp
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008293:Malates / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D062907:Oxaloacetic Acid / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D011817:Rabbits; D012402:Rotenone / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D008293:Malates; D012402:Rotenone; D062907:Oxaloacetic Acid; D018698:Glutamic Acid; C030298:malic acid; D000637:Transaminases; D010100:Oxygen
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