title: Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy.
abstract: Oxidative stress-induced mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in peripheral neurons is considered to be important in the development of diabetic neuropathy. Mitochondrial transcription factor A (TFAM) wraps mtDNA and promotes mtDNA replication and transcription. We studied whether overexpression of TFAM reverses experimental peripheral diabetic neuropathy using TFAM transgenic mice (TFAM Tg) that express human TFAM (hTFAM). Levels of mouse mtDNA and the total TFAM (mouse TFAM + hTFAM) in the dorsal root ganglion (DRG) increased by approximately twofold in the TFAM Tg mice compared with control (WT) mice. WT and TFAM Tg mice were made diabetic by the administration of streptozotocin. Neuropathy end points were motor and sensory nerve conduction velocities, mechanical allodynia, thermal nociception, and intraepidermal nerve fiber density (IENFD). In the DRG neurons, mtDNA copy number and damage to mtDNA were quantified by qPCR, and TFAM levels were measured by Western blot. Mice with 16-wk duration of diabetes developed motor and sensory nerve conduction deficits, behavioral deficits, and intraepidermal nerve fiber loss. All of these changes were mostly prevented in diabetic TFAM Tg mice and were independent of changes in blood parameters. Mice with 16 wk of diabetes had a 40% decrease in mtDNA copy number compared with nondiabetic mice (P < 0.01). Importantly, the mtDNA copy number in diabetic TFAM Tg mice reached the same level as that of WT nondiabetic mice. In comparison, there was upregulation of mtDNA and TFAM in 6-wk diabetic mice, suggesting that TFAM activation could be a therapeutic strategy to treat peripheral neuropathy.
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System;
authors.forename: Krish
authors.initials: K
authors.lastname: Chandrasekaran
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System; Principal Investigator, Preclinical Division, Syngene International Ltd., Bangalore, India;
authors.forename: Muragundla
authors.initials: M
authors.lastname: Anjaneyulu
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System; Daiichi Sankyo Co. Ltd., Tokyo, Japan; and.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System;
authors.forename: Joungil
authors.initials: J
authors.lastname: Choi
authors.affiliation: Veterans Affiars Maryland Health Care System;
authors.forename: Avinash Rao
authors.initials: AR
authors.lastname: Sagi
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System;
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University, Maidashi Higashi-ku, Fukuoka, Japan.
authors.forename: Tamomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Department of Neurology, University of Maryland, Baltimore, Maryland; Veterans Affiars Maryland Health Care System; JRussell@som.umaryland.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Russell
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000235:genetics; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins / Q000502:physiology*; D063306:Mitophagy / Q000235:genetics*; D013311:Streptozocin; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D013311:Streptozocin
keywords: diabetes; mitochondria; mitochondrial transcription factor A; neuropathy