Han 2017 MiP2017
Metabolic syndrome is the major risk factor for type 2 diabetes and associated retinopathy (DR), which is the leading cause of blindness in the working age population . While most studies have focused on pathological changes and management of blood-retina barriers, there is increasing attention on the contribution of mitochondria. The present study aimed at directly testing whether defects in oxidative phosphorylation (OXPHOS) in the retina and the underlying retinal pigment epithelium (RPE) might precede the development of hyperglycemia and associated vascular changes in metabolic syndrome.
Nile grass rats (Arvicanthis niloticus) were fed standard rodent chow, which was associated with hyperinsulinemia at 2 month, followed by hyperglycemia by 6 month, and retinal pericyte drop by 18 month. Controls were fed a high fiber low-calorie diet, which prevented hyperglycemia up to 18 month. Metabolic syndrome progression was confirmed using systemic markers. High-resolution respirometry (O2k-FluoRespirometer; Oroboros Instruments) was used to measure mitochondrial function in retina and RPE homogenates isolated from individual Nile grass rats. The multiple substrates-inhibitor protocol allowed the measurement of OXPHOS capacity while feeding electrons into the NADH-pathway, the combined NADH & Succinate-pathway (maximal OXPHOS capacity), the succinate-pathway and the Complex IV single step. In addition, LEAK state was measured in the absence of ADP and the integrity of the outer mitochondrial membrane was assessed by addition of exogenous cytochrome c. Citrate synthase activity was used as a marker of mitochondrial content.
Animals fed standard chow developed hyperinsulinemia at 2 month and hyperglycemia at 6 month whereas control animals maintained normoglycemia throughout their lifespan and developed hyperinsulinemia at 18 month. BMI of standard chow animals were constantly higher than control at all time points. Retinal mitochondria responded more readily to progression of metabolic syndrome. Before the onset of hyperglycemia, the 2 months old chow fed animals displayed increased contribution of NADH-pathway to maximal oxidative phosphorylation capacity as well greater loss of mitochondrial membrane integrity . In contrast, the RPE mitochondria of chow-fed animals did not display difference to that of control animals. Interestingly, however, age had significant effect on LEAK, NADH- and Succinate-pathway respiration in the RPE of chow-fed animals, but not in the retina. Citrate synthase activity did not differ between ages in neither of ocular tissues.
Mitochondria from retina and RPE display different functional response to developing metabolic syndrome. This different ocular mitochondrial properties should be appreciated for development of an efficient mitochondria-targeting therapies against DR.
Labels: MiParea: Exercise physiology;nutrition;life style Pathology: Other
Organism: Rat Tissue;cell: Nervous system
Coupling state: LEAK, OXPHOS Pathway: S, CIV, NS
- Han T(1), Sauve Y(1,2), Lemieux H(3)
- Dept Ophthalmol Vis Sci
- Dept Physiol
- Facu Saint-Jean; Univ Alberta, Canada. - [email protected]
- Lee, R, Wong TY, Sabanayagam C (2015) Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vision (London, England) 2:17.