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.

Mitochondrial pathways to cardiac recovery: TFAM

“…Diabetic TFAM-transgenic mice showed significant prevention of downstream damage compared to mitochondrial DNA damage of WT mice [159]. Findings include that overexpression of TFAM inhibited rotenone-induced mt ROS production and nuclear factor-kappaB (NFkB) translocation.…”

A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug‐Induced Peripheral Neuropathy

“…Some of the genes identified using the NID network have strong associations to a neuropathic mechanism. For instance, impaired function of neuronal mitochondria has been proposed as having an important role in the development of neuropathies . One of the genes identified in this work is ganglioside‐induced differentiation‐associated protein 1 ( GDAP1 ), a gene that encodes an outer mitochondrial membrane protein.…”

“…For instance, impaired function of neuronal mitochondria has been proposed as having an important role in the development of neuropathies. 29 One of the genes identified in this work is ganglioside-induced differentiation-associated protein 1 (GDAP1), a gene that encodes an outer mitochondrial membrane protein. It acts as a regulator of mitochondrial fission, 30 and there is abundant evidence associating alterations of this gene to the hereditary Charcot-Marie-Tooth neuropathy (CMT).…”

mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

“…Reduced Mt bioenergetic function and increased oxidative stress are significant contributors in diabetic neuropathy . Key transcription factors, for example, the silent information regulator protein 1 (SIRT 1) ‐ Peroxisome proliferator‐activated receptor‐gamma coactivator 1 α (PGC‐1 α ) ‐ mitochondrial transcription factor A (TFAM) axis, are critical in regulating Mt function in response to oxidative stress in experimental diabetic neuropathy . SIRT1 in neurons is neuroprotective, is important in axonal regeneration, and deacetylates PGC‐1 α .…”

“…The 35‐kDa PGC‐1 α isoform is critical for reducing oxidative stress and regulation of key Mt β ‐oxidation enzymes . The transcription factor activated by SIRT1‐ PGC‐1 α is TFAM, which promotes replication and transcription of mitochondrial DNA (mtDNA), wraps Mt DNA to protect it from oxidative stress and reduces experimental diabetes‐induced neuropathy …”