Intracellular pH Modulates Autophagy and Mitophagy

Alexey V Berezhnov,Marc P.M Soutar,Evgeniya I Fedotova,Maria S Frolova,Helene Plun-Favreau,Valery P Zinchenko,Andrey Y Abramov

doi:10.1074/jbc.m115.691774

Abstract

The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control.

Highlights

Continuous ATP production is essential for cell survival
Mitochondrial autophagy2 plays a role in the quality control of this organelle, whereas dysfunction in mitophagy can lead to an increase in the number of damaged mitochondria that can trigger the activation of cell death pathways [3, 4]
High Concentrations of FCCP and Nigericin Reduce pHcyt— High dose CCCP or FCCP (10 ␮M) treatment of cells is the most common method for the activation of mitophagy. These treatments induce dissipation of mitochondrial membrane potential (⌬⌿m), and this effect is believed to be important for the initiation of PTEN-induced kinase 1 (PINK1) accumulation and the recruitment of Parkin for triggering mitophagy

Summary

Intracellular pH Modulates Autophagy and Mitophagy*

Mitochondrial autophagy (mitophagy) plays a role in the quality control of this organelle, whereas dysfunction in mitophagy can lead to an increase in the number of damaged mitochondria that can trigger the activation of cell death pathways [3, 4]. The methods used to activate mitophagy involve the treatment of cells with a high (10 ␮M) concentration of the protonophore CCCP or FCCP [8, 11], which uncouples oxidative phosphorylation from ATP production. This observation forms the basis for mitochondrial depolarization as a hypothesis for mitophagy initiation. We found that acidification of cytosol caused by nigericin can trigger autophagy and mitophagy

Experimental Procedures

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Discussion