Mitochondrial transcription factor a regulation of mitochondrial degeneration in experimental diabetic neuropathy

Krish Chandrasekaran, Muragundla Anjaneyulu, Tatsuya Inoue, Joungil Choi, Avinash Rao Sagi, Chen Chen, Tomomi Ide, James W. Russell

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E132-E141
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume309
Issue number2
DOIs
Publication statusPublished - Jul 15 2015

Fingerprint

Diabetic Neuropathies
Transcription Factors
Mitochondrial DNA
Transgenic Mice
Neural Conduction
Spinal Ganglia
Peripheral Nervous System Diseases
Nerve Fibers
Neurons
Nociception
Hyperalgesia
Streptozocin
DNA Replication
DNA Damage
Oxidative Stress
Up-Regulation
Hot Temperature
Western Blotting

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Mitochondrial transcription factor a regulation of mitochondrial degeneration in experimental diabetic neuropathy. / Chandrasekaran, Krish; Anjaneyulu, Muragundla; Inoue, Tatsuya; Choi, Joungil; Sagi, Avinash Rao; Chen, Chen; Ide, Tomomi; Russell, James W.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 309, No. 2, 15.07.2015, p. E132-E141.

Research output: Contribution to journalArticle

Chandrasekaran, Krish ; Anjaneyulu, Muragundla ; Inoue, Tatsuya ; Choi, Joungil ; Sagi, Avinash Rao ; Chen, Chen ; Ide, Tomomi ; Russell, James W. / Mitochondrial transcription factor a regulation of mitochondrial degeneration in experimental diabetic neuropathy. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 309, No. 2. pp. E132-E141.
@article{3c1fe927e58e483d9b365b7fad3a0b7e,
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.",
author = "Krish Chandrasekaran and Muragundla Anjaneyulu and Tatsuya Inoue and Joungil Choi and Sagi, {Avinash Rao} and Chen Chen and Tomomi Ide and Russell, {James W.}",
year = "2015",
month = "7",
day = "15",
doi = "10.1152/ajpendo.00620.2014",
language = "English",
volume = "309",
pages = "E132--E141",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Mitochondrial transcription factor a regulation of mitochondrial degeneration in experimental diabetic neuropathy

AU - Chandrasekaran, Krish

AU - Anjaneyulu, Muragundla

AU - Inoue, Tatsuya

AU - Choi, Joungil

AU - Sagi, Avinash Rao

AU - Chen, Chen

AU - Ide, Tomomi

AU - Russell, James W.

PY - 2015/7/15

Y1 - 2015/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937560626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937560626&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00620.2014

DO - 10.1152/ajpendo.00620.2014

M3 - Article

VL - 309

SP - E132-E141

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -