PGC-1α regulation of mitochondrial degeneration in experimental diabetic neuropathy

NEUROBIOLOGY OF DISEASE

卷:64

Article

Choi, Joungil^1,2  Chandrasekaran, Krish^1,2  Inoue, Tatsuya^1,2  Muragundla, Anjaneyulu^1,2  Russell, James W.^1,2 

[1] Univ Maryland, VA Maryland Hlth Care Syst, Baltimore, MD 21201 USA

[2] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA

关键词: Neuropathy;    Mitochondria;    Diabetes;    Oxidative stress;   

DOI  :  10.1016/j.nbd.2014.01.001

来源: Elsevier

【 摘 要 】

Mitochondrial degeneration is considered to play an important role in the development of diabetic peripheral neuropathy in humans. Mitochondrial degeneration and the corresponding protein regulation associated with the degeneration were studied in an animal model of diabetic neuropathy. PGC-1 alpha and its-regulated transcription factors including TFAM and NRF1, which are master regulators of mitochondrial biogenesis, are significantly downregulated in streptozotocin diabetic dorsal root ganglion (DRG) neurons. Diabetic mice develop peripheral neuropathy, loss of mitochondria, decreased mitochondrial DNA content and increased protein oxidation. Importantly, this phenotype is exacerbated in PGC-l alpha(-/-) diabetic mice, which develop a more severe neuropathy with reduced mitochondrial DNA and a further increase in protein oxidation. PGC-l alpha (-/-) diabetic mice develop an increase in total cholesterol and triglycerides, and a decrease in TFAM and NRF1 protein levels. Loss of PGC-1 alpha causes severe mitochondrial degeneration with vacuolization in DRG neurons, coupled with reduced state 3 and 4 respiration, reduced expression of oxidative stress response genes and an increase in protein oxidation. In contrast, overexpression of PGC-1 alpha in cultured adult mouse neurons prevents oxidative stress associated with increased glucose levels. The study provides new insights into the role of PGC-1 alpha in mitochondrial regeneration in peripheral neurons and suggests that therapeutic modulation of PGC-1 alpha function may be an attractive approach for treatment of diabetic neuropathy. Published by Elsevier Inc.

【 授权许可】

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