p62-Nrf2-p62 Mitophagy Regulatory Loop as a Target for Preventive Therapy of Neurodegenerative Diseases

Abstract

Turnover of the mitochondrial pool due to coordinated processes of mitochondrial biogenesis and mitophagy is an important process in maintaining mitochondrial stability. An important role in this process is played by the Nrf2/ARE signaling pathway, which is involved in the regulation of the expression of genes responsible for oxidative stress protection, regulation of mitochondrial biogenesis, and mitophagy. The p62 protein is a multifunctional cytoplasmic protein that functions as a selective mitophagy receptor for the degradation of ubiquitinated substrates. There is evidence that p62 can positively regulate Nrf2 by binding to its negative regulator, Keap1. However, there is also strong evidence that Nrf2 up-regulates p62 expression. Thereby, a regulatory loop is formed between two important signaling pathways, which may be an important target for drugs aimed at treating neurodegeneration. Constitutive activation of p62 in parallel with Nrf2 would most likely result in the activation of mTORC1-mediated signaling pathways that are associated with the development of malignant neoplasms. The purpose of this review is to describe the p62-Nrf2-p62 regulatory loop and to evaluate its role in the regulation of mitophagy under various physiological conditions.

Keywords: Nrf2; mitochondria; mitophagy; neurodegenerative disease; p62; regulatory loop.

Figure 1

Scheme of p62-Nrf2 loop with protein and gene structure. KIR of p62 interacts with the Kelch repeat of KEAP1 protein and inhibits its activity. Kelch repeat interacts with the Neh2 domain of the Nrf2 protein and inactivates it. Free Nrf2 can interact with the ARE region of the SQSTM1 gene and increase its expression. A. mRNA structure of SQSTM1 of humans. mRNA contains 1352 protein-coding bp and includes 8 exons. B. Domain structure of p62 protein of human (440 aa). Phox and Bem1p (PB1)—4–102 aa; ZZ-type zinc finger domain (ZZ)—126–168 aa; TRAF6 binding domain (TB)—228–233 aa; LC3 interacting region (LIR)—336–341 aa; KEAP1 interacting region (KIR)—347–352 aa; ubiquitin-associated domain (UBA)—379–439 aa. C. Domain structure of KEAP1 protein of human (624 aa). BTB domain (BTB)—78–178 aa; intervening region (IVR)—179–327 aa; Kelch repeat (Kelch1–Kelch6)—327–611 aa. D. Domain structure of KEAP1 protein of human (605 aa). Neh domains. Neh2—16–86 aa; Neh4—112–134 aa; Neh5—183–201 aa; Neh7—209–316 aa; Neh6—338–388 aa; Neh1—435–562 aa; Neh3—563–605 aa. E. SQSTM1 gene structure of humans. Gene contains 8 exons. 1st exon (0–237 bp); 2nd exon (2054–2149 bp); 3rd exon (2954–3183 bp); 4th exon (3278–3419 bp); 5th exon (4249–4322 bp); 6th exon (12128–12342 bp); 7th exon (12683–12878 bp); 8th exon (15532–17147 bp). SQSTM1 gene contains ARE region at (−1306)–(−1295) bp.

Figure 2

Two regulatory loops for mitochondria turnover. Nrf2—PGC1α—p38—GSK3β—Nrf2 loop and Nrf2—NRF1 interaction regulate of mitochondrial biogenesis. Nrf2—p62—KEAP1—Nrf2 loop and Nrf2—PINK1 interaction regulate of mitochondrial biogenesis.