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Dysregulation of p53 and Parkin Induce Mitochondrial Dysfunction and Leads to the Diabetic Neuropathic Pain.

Abstract：

:p53 and parkin are involved in mitochondrial quality control. The present study aimed to characterize the functional significance of parkin/p53 in the development of mitochondrial dysfunction and the pathophysiology of neuropathic pain in type I diabetes. Type I diabetes was induced in mice (N = 170) using streptozotocin (STZ). Pifithrin-α, a selective p53 inhibitor, was administered to assess its effects on diabetic pain hypersensitivity, parkin expression and mitochondrial function. Expressions of parkin and p53, mitochondrial number and level of reactive oxygen species (ROS) in the dorsal root ganglion (DRG) were analyzed by immunohistochemistry, western blotting and real time PCR. Separately, mice were treated using intravenous methylglyoxal, then pain hypersensitivity and p53/parkin expression in the DRG were assessed. Mitochondrial membrane potential was also analyzed in cultured DRG neurons treated with methylglyoxal. Mice developed pain hypersensitivity for 3 weeks after STZ treatment. p53 expression was significantly increased (control, 0.68 ± 0.122; STZ, 1.88 ± 0.21) whereas parkin expression was significantly reduced (control, 1.02 ± 0.17; STZ, 0.59 ± 0.14), in the DRG after STZ treatment. Inhibition of p53 by pifithrin-α prevented STZ-induced pain hypersensitivity and parkin downregulation. Pifithrin-α also inhibited STZ-induced reductions in mitochondrial number and accumulation of mitochondrial ROS. Methylglyoxal elicited pain hypersensitivity and alteration of p53/parkin expression, similar to STZ. Methylglyoxal also decreased mitochondrial membrane potential in cultured DRG neurons. Alteration of p53/parkin expression produces mitochondrial dysfunction and ROS accumulation, leading to pain hypersensitivity in diabetic or methylglyoxal treated mice. Methylglyoxal produces neurological derangements similar to diabetes, via direct mechanisms on DRG neurons.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Yamashita A,Matsuoka Y,Matsuda M,Kawai K,Sawa T,Amaya F

doi

10.1016/j.neuroscience.2019.07.045

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

9-19

eissn

0306-4522

issn

1873-7544

pii

S0306-4522(19)30536-6

journal_volume

416

pub_type

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Dysregulation of p53 and Parkin Induce Mitochondrial Dysfunction and Leads to the Diabetic Neuropathic Pain.