PINK1 mediates spinal cord mitophagy in neuropathic pain

Abstract

Min-Hee Yi,1 Juhee Shin,2,3 Nara Shin,2,3 Yuhua Yin,2,4 Sun Yeul Lee,4 Cuk-Seong Kim,3,5 Sang Ryong Kim,6 Enji Zhang,7 Dong Woon Kim2,31Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; 2Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea; 3Department of Medical Science, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea; 4Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon 301-747, South Korea; 5Department of Physiology, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea; 6School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Republic of Korea; 7Department of Anesthesia Medicine, Yanbian University Hospital, Yanbian 133000, People’s Republic of ChinaBackground: Mitophagy is the selective engulfment of mitochondria by autophagosomes and the subsequent mitochondrial catabolism by lysosomes. Evidence has suggested an important role for mitochondrial dynamics and mitophagic flux in the development of many different neurodegenerative diseases.Objectives: The potential role of the mechanism underlying mitochondrial dynamics and mitophagic flux as it may relate to neuropathic pain is not well understood. This is a disease that largely remains an area of mechanistic uncertainty. PINK1 is a PTEN-induced mitochondrial kinase that can be selectively activated under mitochondrial stress conditions and lead to the induction of mitophagy.Materials and methods: A neuropathic pain rat model was established via spinal nerve ligation (SNL) and nociception was assayed via the von Frey filament method. Increased expression of PINK1 and the mechanism of mitophagy was detected in GABAergic interneurons of dorsal horn neurons of mice that underwent L5 SNL in comparison to control mice counterparts (n=8, P<0.001) by Western blotting, immunohistochemistry and double immunofluorescence staining.Results: Elevated expression of PINK1 appeared to localize selectively to GABAergic interneurons, particularly within autophagic mitochondria as evidenced by co-localization studies of PINK1 with BECN1, LC3II and COX IV on immunofluorescent microscopy. Furthermore, we also detected a significant increase in autophagosomes in dorsal horn neurons of SNL mice and this was consistent with increased autophagic activity as measured by the p62 autophagic substrate.Conclusion: These results demonstrate that neuropathic pain causes aberrant mitophagic flux selectively in GABAergic interneurons and provide evidence implicating mitophagy as an important area of future molecular studies to enhance our understanding of neuropathic pain.Keywords: neuropathic pain, PINK1, mitophagy, GABAergic interneuron, autophagosome

Keywords

• Neuropathic Pain
• PINK1
• Mitophagy
• GABAergic interneuron.
• Autophagosome