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Julia M. dos Santos, Renu Kowluru; Mitochondrial Biogenesis And The Development Of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4451.
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© ARVO (1962-2015); The Authors (2016-present)
Mitochondria dysfunction plays an important role in the development of diabetic retinopathy. Mitochondrial DNA (mtDNA) is damaged in the retina and its capillary cells in diabetes initiating a vicious cycle of increased superoxide radicals. Regulation of superoxide levels by mitochondrial superoxide dismutase (MnSOD) attenuates diabetes-induced impairment in complex III and protects mitochondrial integrity. MtDNA replication and transcription are tightly controlled by nucleus-mitochondria signaling. Mitochondrial biogenesis is regulated by nuclear encoded peroxisomal proliferators activator receptor co-activator (PGC-1)-nuclear respiratory factor 1 (NRF1)- mitochondria transcription factor A (TFAM) pathway. Our previous studies have shown that the retinal proteins encoded by mtDNA are subnormal in diabetes. The aim of this study is to elucidate the role of nuclear-mitochondrial interaction in the development of diabetic retinopathy.
Retina from MnSOD transgenic mice (Tg) and their wildtype (WT) littermates, diabetic (streptozotocin-induced) or non diabetic, were analyzed by RT-PCR for gene expression of PGC-1, NRF-1 and TFAM. Expression of these proteins was quantified in mitochondria by western blot technique, and protein-protein binding between TFAM and mitochondrial chaperone, heat shock protein 60 (HSP60) was evaluated by co-immunoprecipitation.
Diabetes in WT mice increased gene transcripts of PGC-1, NRF1 and TFAM in the retina, but mitochondrial accumulation of TFAM was significantly decreased. In the same retina, the binding of HSP60 and TFAM was also subnormal compared to the values obtained from age-matched WT-non diabetic mice. Overexpression of MnSOD, which we have shown to prevent the development of diabetic retinopathy in mice, protected the retina from decreased mitochondrial accumulation of TFAM, and the binding between HSP60 and TFAM was also similar to the values obtained from WT or Tg non-diabetic mice.
Diabetes induces increase in the nuclear encoded transcription factors important in the mitochondria biogenesis, but TFAM, pivotal in coordinating the expression of proteins in the nuclear and mitochondrial genomes, fails to reach the target due to its decreased transport to the mitochondria. Understanding the mechanism(s) by which diabetes impairs the transport of the transcriptional factors critical in mitochondrial biogenesis should help identify targets for future therapeutic to inhibit/prevent this blinding disease.
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