The pharmacological regulation of cellular mitophagy.

Nikolaos D Georgakopoulos,Geoff Wells,Michelangelo Campanella

doi:10.1038/nchembio.2287

Abstract

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications.

Highlights

Mitochondrial autophagy, known as mitophagy, governs the elimination of dysfunctional or superfluous mitochondria and is fundamental to both mitochondrial and cellular homeostasis.[1]
PINK1 activates the E3 Ub ligase Parkin via mechanism involving the phosphorylation of both Parkin and its substrate Ub at Ser65.5,6 Once localized on mitochondria, Parkin acts in concert with PINK1 to amplify the initial signal by decorating mitochondria with Ub chains, which are sequentially phosphorylated by PINK1 (Figure 1c).[6]
The accumulation of pSer65-Ub chains on the outer mitochondrial membrane (OMM) triggers the recruitment of the autophagy receptors optineurin (OPTN) and nuclear dot protein 52 (NDP52), which promote the biogenesis of phagophores in close proximity to mitochondria by recruiting the autophagy-initiating factors ULK1, DFCP1 (Double FYVE-domain containing protein 1) and WIPI1 (WD repeat domain, phosphoinositide interacting 1).[6]

Summary

Introduction

Mitochondrial autophagy, known as mitophagy, governs the elimination of dysfunctional or superfluous mitochondria and is fundamental to both mitochondrial and cellular homeostasis.[1].

Results

Conclusion