Poly (ADP-ribose) polymerase 1-mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model.

Abstract

Studies have shown that poly (ADP-ribose) polymerase 1 (PARP1) is involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy-related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1-mediated mitophagy blockade in a leptin gene-mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes-induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes-induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1-induced defective mitophagy of DRG neurons is a key mechanism in diabetes-induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.

• Authors: Pengfei Yuan, Fuhu Song, Pian Zhu, Keke Fan, Qinming Liao, Lijin Huang, Zhongjie Liu
• Journal: Journal of neurochemistry (J Neurochem) Vol. 162 Issue 3 Pg. 276-289 (08 2022) ISSN: 1471-4159 [Electronic] England
• PMID: 35263449 (Publication Type: Journal Article)
• Copyright: © 2022 International Society for Neurochemistry.

Chemical References

• Adenosine Diphosphate
• Ribose

Topics

• Adenosine Diphosphate (metabolism)
• Animals
• Diabetes Mellitus (metabolism, pathology)
• Diabetic Neuropathies
• Ganglia, Spinal (metabolism)
• Mice
• Mitophagy
• Ribose