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The pharmacological regulation of cellular mitophagy

Nature Chemical Biology volume 13, pages 136–146 (2017)Cite this article

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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.

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Figure 1: PINK1–parkin-mediated mitophagy.
Figure 2: PINK1–parkin-independent mechanisms of mitophagy.
Figure 3: Activation of Ub-dependent mitophagy by modulators of the PINK1–parkin pathway.
Figure 4: The model of mitophagy induction via PMI, SIRT1 activators and iron chelators.
Figure 5: Chemical approaches to inhibit the Keap1-mediated degradation of Nrf2.

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Acknowledgements

The research activities led by M.C. are supported by the following funders, which are gratefully acknowledged: the Biotechnology and Biological Sciences Research Council (grant numbers BB/M010384/1 and BB/N007042/1); the Medical Research Council (grant number G1100809/2), Bloomsbury Colleges Consortium PhD Studentship Scheme; BBSRC iCase Studentship Scheme; The Petplan Charitable Trust; The Umberto Veronesi Foundation; Marie Curie Actions and LAM–Bighi Grant Initiative. G.W. acknowledges Cancer Research UK (C9344/A10268), the BBSRC (BB/L01923X/1) and UCL School of Pharmacy for financial support.

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  1. Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK

    Nikolaos D Georgakopoulos & Michelangelo Campanella

  2. UCL School of Pharmacy, London, UK

    Nikolaos D Georgakopoulos & Geoff Wells

  3. University College London Consortium for Mitochondrial Research, London, UK

    Michelangelo Campanella

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Correspondence to Michelangelo Campanella.

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N.D.G. and G.W. are shareholders in Keregen Therapeutics Ltd, a small and medium-sized enterprise (SME) with a research interest in Nrf2 inducing compounds.

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Georgakopoulos, N., Wells, G. & Campanella, M. The pharmacological regulation of cellular mitophagy. Nat Chem Biol 13, 136–146 (2017). https://doi.org/10.1038/nchembio.2287

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