Renal mitochondrial damage and protein modification in type-2 diabetes

Area of Science:

• Nephrology
• Mitochondrial Biology
• Diabetic Complications

Background:

• Mitochondrial redox stress and membrane permeability are implicated in diabetic kidney disease.
• The link between intra-renal mitochondrial oxidative stress and protein modification causing membrane permeability is not fully understood.

Purpose of the Study:

• To investigate the role of intra-renal mitochondrial oxidative stress in protein modification and membrane permeability in type-2 diabetes.
• To determine if mitochondrial oxidative stress induces mitochondrial protein modification and leakage.

Main Methods:

• Type-2 diabetes induced in C57BL/6J mice via a high-calorie, high-fat diet.
• Kidney tissue subjected to subcellular fractionation, Western blot, and 2-D proteomics.
• Analysis of mitochondrial protein expression (NOX-4, SOD-1, SOD-2) and post-translational modifications (nitrotyrosine).

Main Results:

• Diabetes increased mitochondrial NADPH oxidase-4 (NOX-4) and decreased superoxide dismutase-1, 2 (SOD-1, 2) expression.
• Mitochondrial membrane permeability was compromised, evidenced by cytochrome c and prohibitin leakage into the cytosol.
• 2-D Western blots showed increased nitrotyrosine modification of mitochondrial proteins in diabetic mice.

Conclusions:

• Diabetes-induced intra-renal mitochondrial oxidative stress increases mitochondrial membrane permeability.
• Nitrotyrosine generation is a key protein modification associated with mitochondrial dysfunction in diabetic kidneys.