Molecular understanding of AMPK and PINK1 signaling pathways under mitochondrial damages

Abstract

Mitochondria are crucial intracellular organelles involved in ATP production, calcium regulation, and innate immune responses. Mitochondrial damages are associated with common neurodegenerative diseases including Parkinson’s disease (PD). Therefore, it is important that how cells respond to mitochondrial damages, in terms of cellular signal transduction, to understand and treat such diseases. Especially, CCCP-induced mitochondrial damages reveal induction of autophagy as well as inhibition of cell growth as a defense mechanism of the cell. It has been supposed that AMPK, a crucial energy sensor, mediates this defense system directly or indirectly through its downstream, mTORC1. In addition, recent reports showed that CCCP-induced autophagy including mitophagy is dependent on PINK1/Parkin pathway, one of signaling systems involved in genetic PD. Firstly, I examined whether AMPK, a crucial energy sensor, is essential for CCCP-induced autophagy. Unexpectedly, I observed that CCCP, independently of AMPK, downregulates mTORC1 and promotes autophagy including mitophagy. Furthermore, I performed the screening to find another crucial kinase for CCCP-induced mitochondrial damages using Drosophila dsRNA kinase library, and had not obtained any candidate kinases. It infers that CCCP-dependent mitochondrial damages are mediated by other proteins in new functional groups, not in protein kinases to control mTORC1 activity and autophagy. Secondly, I investigated whether calcium is required for CCCP-induced PINK1/Parkin pathway. Intriguingly, CCCP-dependent accumulation of full-length PINK1 and Parkin translocation at mitochondria were inhibited by intracellular calcium chelators including BAPTA/AM and EGTA/AM. Calcium deprivation, independently of CCCP, mainly decreased full-length PINK1 resulting in cleaved PINK1. The detailed molecular mechanism of how calcium regulates the proteolytic processes of full-length PINK1 remains to be further investigated. Taken together, my studies on AMPK and PINK1 signaling pathways under CCCP-induced mitochondrial damages will be helpful to understand the pathophysiological mechanism of PD.