Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart

Abstract

Mitochondrial quality is a crucial determinant of cell viability, and mitochondrial autophagy plays a central role in this control mechanism. Based on studies in yeast, numerous investigations of this process have been conducted, and the framework of mammalian mitochondrial autophagy is progressively appearing. However, many enigmas about the molecular mechanisms involved remain unsolved. Furthermore, the pathological significance of mitochondrial autophagy in the heart remains largely unclear. In this review, we discuss the current understanding of mitochondrial autophagy in mammals with reference to that in yeast. Regarding the process in yeast, some points of uncertainty have arisen. We also summarize recent advances in the research of autophagy and mitochondrial autophagy in the heart. This article is a part of a review series on Autophagy in Health and Disease.

Keywords: Parkin; Pink1; autophagy; mitophagy.

Fig. 1

The mechanism of mitophagy in yeast. CK2 directly phosphorylates Atg32 at Ser 114 and Ser 119 when cells are cultured in lactate medium and then shifted to nitrogen starvation medium supplemented with glucose. This phosphorylation, especially phosphorylation at Ser 114, is critically important for the Atg32-Atg11 interaction, which is required for the delivery of mitochondria to the phagophore assembly site (PAS). Atg11 recruits the mitochondrial fission complex, which consists of Dnm1, Fis1, Mdv1 and Caf4. Subsequently, mitochondrial fission and mitophagy take place. Mitochondrial division is important for mitophagy in yeast.

Fig. 2

LC3-interacting molecules act as receptors for autophagosomes on mitochondria. (A, B) Nix and Bnip3, BH3-only proteins, interact with LC3 through the LIR and regulate mitochondrial autophagy. Oxidative stress induces homodimerization and activation of Bnip3. Phosphorylation of the LIR in Bnip3 promotes the association between Bnip3 and LC3. (C) Under hypoxia, dephosphorylation of FUNDC1 at Ser 13 or Tyr 18 stabilizes the interaction between FUNDC1 and LC3. (D) Cardiolipin, a phospholipid of the IMM, translocates to the mitochondrial surface in response to mitochondrial damage. The externalized cardiolipin binds to LC3.

Fig. 3

The mechanism of mitochondrial autophagy mediated by Pink1-Parkin in mammalian cells. Mitochondrial proteases and peptidases continuously degrade Pink1 in intact mitochondria. However, Pink1 is not imported to the inner membrane and is not cleaved in depolarized mitochondria. Pink1 then accumulates at the outer membrane and recruits Parkin. Mfn2 phosphorylated by Pink1 acts as a receptor for Parkin on mitochondria. Parkin ubiquitinates multiple proteins of the outer membrane. These ubiquitinated proteins are recognized by p62, a ubiquitin- and LC3-binding adaptor protein, followed by mitochondrial autophagy.