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Julia M. Santos, Renu A. Kowluru; Retinal Mitochondrial Transport Machinery And Decreased Mitochondria Biogenesis In The Development Of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5417.
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In the development of diabetic retinopathy, retinal mitochondria biogenesis is impaired, the nucleus-encoded mitochondria transcription factor A (TFAM) fails to reach to the mitochondria, the site of its action, and the electron transport system is compromised. Nuclear-encoded proteins, important in mitochondria biogenesis, are transported to the mitochondria mainly by cytosolic chaperone (Hsp70), and imported into the mitochondria via translocation complexes in the outer and inner mitochondrial membrane (TOM and TIM respectively). The aim of this study is to investigate the role of the transport proteins in the impaired retinal mitochondria biogenesis in diabetes.
Hsp70, TOM70, TOM40 and TIM44 were quantified in the retina streptozotocin-induced diabetic rats (~12 months duration). The binding of TFAM with Hsp70, TOMs and TIM44 was determined by co-immunoprecipitation and that with mtDNA by chromatin immunopreciptation.
Diabetes significantly decreased Hsp70, TOM70, TOM40 and TIM44 expressions in the retina. The binding of TFAM with the Hsp70, and also with the components of the mitochondria translocase system, was attenuated compared to that observed in the retina from age-matched normal rats. Consistent with this, the binding of TFAM with retinal mtDNA was also subnormal.
Subnormal chaperon and transport machinery in diabetes impairs the transport of TFAM into the retinal mitochondria, and decreased binding of TFAM with the mtDNA results in attenuated mitochondria biogenesis initiating a vicious cycle of dysfunctional electron transport machinery. The regulation of the transporter proteins in diabetes could help maintain normal mitochondria biogenesis, and inhibit the development of diabetic retinopathy.
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