Han 2017 Abstract IOC122

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Retinal mitochondria respiration defects precede hyperglycemia onset in type 2 diabetes.

Link: Mitochondr Physiol Network 22.01

Han WH, Kuny S, Sauve Y, Lemieux H (2017)

Event: IOC122

There is increasing evidence linking retinal mitochondria defects with development and progression of diabetic retinopathy. We tested the hypothesis that defects in retinal mitochondrial oxidative phosphorylation (OXPHOS) might precede the development of hyperglycemia and associated vascular changes in type 2 diabetes.

We used male Nile grass rats (Arvicanthis niloticus), which when fed standard rodent chow, undergo hyperinsulinemia at 2 month, followed by hyperglycemia by 6 month and retinal pericyte drop at 18 month. Controls were fed a high fiber low-calorie diet, which prevented hyperglycemia up to 18 month. High-resolution respirometery (Oxygraph 2k; Oroboros) allowed measuring mitochondrial function in retina homogenates isolated from individual Nile grass rats (n=6-11 animals per group). Specific aspects of mitochondrial respiration were isolated using a multiple substrates-inhibitor protocol: 1) NADH- and succinate-dependent respiration pathway (N- and S-pathway); 2) maximal cytochrome c oxidase (COX) capacity; 3) integrity of the outer mitochondrial membrane under addition of exogenous cytochrome c, cytochrome c control factor (CcCF). Respirometery parameters data were expressed as flux control ratios (FCR), the respiration rate was normalized against maximal OXPHOS capacity. Citrate synthase activity was measured to estimate mitochondrial content. Data are expressed as mean ± SEM. Significance between groups was set at p < 0.05 using the non-parametric Mann-Whitney U-test.

Retinal mitochondrial defects were detected in 2 mo animals that maintained normoglycemia but displayed hyperinsulinemia. An increase in CcCF, indicating compromised membrane integrity, was observed in these animals when compared to controls (5.2 ± 1.5% vs. 1.0 ± 0.5%; p = 0.007; of note: larger value imply less integrity in mitochondrial membranes). Unexpectedly, at 6 mo, hyperglycemic animals had higher membrane integrity relative to control animals (p=0.009). The FCR showed an increase contribution of the N-pathway to overall mitochondrial respiration (0.64 ± 0.01 vs. 0.60 ± 0.01, respectively, p = 0.011).

Prior to hyperglycemia development, hyperinsulinemia is associated with reduced outer membrane integrity and increased N-pathway driven respiration in retinal mitochondria. These findings support that targeting of mitochondria, prior to hyperglycemia, might prevent diabetic retinopathy.

Keywords: Diabetic retinopathy Bioblast editor: Kandolf G O2k-Network Lab: CA Edmonton Lemieux H


Labels: MiParea: Respiration  Pathology: Diabetes 

Organism: Rat  Tissue;cell: Nervous system  Preparation: Homogenate 


Coupling state: OXPHOS  Pathway: NS  HRR: Oxygraph-2k 


Affiliations

Univ Alberta, Edmonton, Canada. - woohyun@ualberta.ca