title: 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.
authors.affiliation: VA Maryland Health Care System, University of Maryland, Baltimore, MD, USA; Department of Neurology, University of Maryland, Baltimore, MD, USA.
authors.forename: Joungil
authors.initials: J
authors.lastname: Choi
authors.affiliation: VA Maryland Health Care System, University of Maryland, Baltimore, MD, USA; Department of Neurology, University of Maryland, Baltimore, MD, USA.
authors.forename: Krish
authors.initials: K
authors.lastname: Chandrasekaran
authors.affiliation: VA Maryland Health Care System, University of Maryland, Baltimore, MD, USA; Department of Neurology, University of Maryland, Baltimore, MD, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: VA Maryland Health Care System, University of Maryland, Baltimore, MD, USA; Department of Neurology, University of Maryland, Baltimore, MD, USA.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Muragundla
authors.affiliation: VA Maryland Health Care System, University of Maryland, Baltimore, MD, USA; Department of Neurology, University of Maryland, Baltimore, MD, USA. Electronic address: JRussell@som.umaryland.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Russell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology*; D005727:Ganglia, Spinal / Q000473:pathology / Q000503:physiopathology; D006609:High Mobility Group Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014617:Vacuoles / Q000473:pathology / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol
keywords: Diabetes; Mitochondria; Neuropathy; Oxidative stress