title: Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes.
abstract: Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and dividing to maintain kidney homoeostasis. In diabetic kidney disease (DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004, Australia Department of Epidemiology & Preventive Medicine, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004, Australia Melinda.Coughlan@bakeridi.edu.au.
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia.
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Penfold
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Higgins
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Centre for Eye Research Australia, Eye and Ear Hospital, East Melbourne, Victoria 3002, Australia.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Van Bergen
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Karly C
authors.initials: KC
authors.lastname: Sourris
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Centre for Eye Research Australia, Eye and Ear Hospital, East Melbourne, Victoria 3002, Australia.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria 8008, Australia Glycation and Diabetes, Mater Research Institute-The University of Queensland, TRI, South Brisbane, QLD 4102, Australia School of Medicine, Mater Clinical School, The University of Queensland, St Lucia, QLD 4067, Australia.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000222:Adaptation, Physiological; D000419:Albuminuria; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology*; D004734:Energy Metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore
keywords: diabetic nephropathy; experimental diabetes; kidney disease; mitochondria