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

Abstract

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-1α 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-1α (−/−) diabetic mice, which develop a more severe neuropathy with reduced mitochondrial DNA and a further increase in protein oxidation. PGC-1α (−/−) diabetic mice develop an increase in total cholesterol and triglycerides, and a decrease in TFAM and NRF1 protein levels. Loss of PGC-1α 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-1α in cultured adult mouse neurons prevents oxidative stress associated with increased glucose levels. The study provides new insights into the role of PGC-1α in mitochondrial regeneration in peripheral neurons and suggests that therapeutic modulation of PGC-1α function may be an attractive approach for treatment of diabetic neuropathy.

Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes

“…Mice having blood glucose levels of 300 mg/dl (16.7 mM) or greater were considered to be diabetic. Our previous study verified and reported that diabetic peripheral neuropathy occurred in the STZ-induced diabetic mice used in this study (Choi et al, 2014). The results showed: 1) a significant increase in glycosylated hemoglobin, indicating prolonged hyperglycemia, 2) impaired nerve conduction studies consistent with neuropathy, 3) loss of the largest myelinated fibers, indicating changes in nerve morphometry, and 4) oxidative injury and mitochondrial dysfunction in dorsal root ganglion neurons (Choi et al, 2014).…”

Diabetes and Cognitive Impairment

“…This suggests upregulation of PINK1 as a possible protective mechanism in AD [70]. Downregulation of PGC-1α in transgenic mice results in Mt dysfunction and spongiform brain pathology [71, 72]. PGC-1α and PINK1 expression is significantly decreased in human AD hippocampus and in mouse diabetic hippocampus [69] supporting the hypothesis that Mt dysfunction may be a shared mechanism in both disorders.…”

Mitochondrial Hormesis and Diabetic Complications

“…Importantly, several studies have found a reduction in PGC1α and reduced mitochondrial biogenesis in islets and human skeletal muscle in patients with diabetes (77,78). Mitochondrial content and PGC1α were also reduced in DRG of STZ-induced type 1 diabetes, and features of neuropathy were exacerbated in PGC1α-deficient diabetic mice (79). A similar reduction in mitochondrial function, content, and PGC1α was also found in the DRG of db / db mice (80).…”