Current opinions on mitophagy in fungi

Abstract

Mitophagy, as one of the most important cellular processes to ensure quality control of mitochondria, aims at transporting damaged, aging, dysfunctional or excess mitochondria to vacuoles (plants and fungi) or lysosomes (mammals) for degradation and recycling. The normal functioning of mitophagy is critical for cellular homeostasis from yeasts to humans. Although the role of mitophagy has been well studied in mammalian cells and in certain model organisms, especially the budding yeast Saccharomyces cerevisiae, our understanding of its significance in other fungi, particularly in pathogenic filamentous fungi, is still at the preliminary stage. Recent studies have shown that mitophagy plays a vital role in spore production, vegetative growth and virulence of pathogenic fungi, which are very different from its roles in mammal and yeast. In this review, we summarize the functions of mitophagy for mitochondrial quality and quantity control, fungal growth and pathogenesis that have been reported in the field of molecular biology over the past two decades. These findings may help researchers and readers to better understand the multiple functions of mitophagy and provide new perspectives for the study of mitophagy in fungal pathogenesis.Abbreviations: AIM/LIR: Atg8-family interacting motif/LC3-interacting region; BAR: Bin-Amphiphysin-Rvs; BNIP3: BCL2 interacting protein 3; CK2: casein kinase 2; Cvt: cytoplasm-to-vacuole targeting; ER: endoplasmic reticulum; IMM: inner mitochondrial membrane; mETC: mitochondrial electron transport chain; OMM: outer mitochondrial membrane; OPTN: optineurin; PAS: phagophore assembly site; PD: Parkinson disease; PE: phosphatidylethanolamine; PHB2: prohibitin 2; PX: Phox homology; ROS, reactive oxygen species; TM: transmembrane.

Keywords: Fission; fungi; mitochondria; mitophagy; pathogenesis; quantity and quality control.

Figure 1.

Receptor-mediated mitophagy in fungi. (A) Structural diagram of the mitophagy receptors in fungi. All three mitophagy receptors contain an AIM domain, the Atg8-family interacting motif (red). Atg32 and SpAtg43 contain a transmembrane (TM) domain for localization (dark purple). MoAtg24 contains a PX domain (light purple) and BAR domain (light red) for localization, and the PX domain is also used to interact with PtdIns3P. The protein sizes are expressed as the numbers of amino acids. (B) Models of mitophagy receptor localization, activation and action. The mitophagy receptor Atg32 of S. cerevisiae is regulated by phosphorylation and dephosphorylation. Atg32 is phosphorylated and activated by CK2 to recruit the autophagy scaffold protein Atg11 and interacts with Atg8 through the AIM motif to recruit the phagophore membrane to selectively enwrap mitochondria for degradation. The mitophagy receptor Atg43 of S. pombe is located in the OMM through the mitochondrial input factor MIM complex, and the mitochondrial input factor Tom70 surrounds and degrades mitochondria by recruiting the core autophagy machinery through the AIM motif. The mitophagy receptor Atg24 of M. oryzae is located in mitochondria via the PX and BAR domains, and interacts with PtdIns3P on the membrane through the PX domain. The S. cerevisiae homolog of Atg24, Snx4, can interact with Atg17.

Figure 2.

Models for regulating mitochondrial morphology and mitophagy in eukaryotes. (A) Schematic diagram of mitochondrial fission and fusion. Mitochondria usually take on various forms, and fission usually occurs before mitophagy. Fragmented mitochondria that are divided from healthy or damaged mitochondria can be recovered and degraded through mitophagy to thereby achieve the quantity and quality control of mitochondria. (B) Schematic diagram of the mitophagy process. 1. Activation of mitophagy receptors on the mitochondrial surface or recruitment of adaptors that mediate ubiquitin-mediated autophagy. 2. Recruit the phagophore by interacting with the core autophagy machinery. 3. Mitochondria to be degraded are sequestered within autophagosomes. 4. Fusion with vacuoles or lysosomes. and 5. Excess and damaged mitochondria are degraded and the breakdown products are released back into the cytosol for reuse.

Figure 3.

Possible models of respiratory chain complex III and related factors regulating mitophagy and autophagy. Inhibitors of respiratory chain complex III, antimycin A, myxothiazol and KCN, regulate mitophagy or autophagy in mammalian cells and in S. cerevisiae cells. In MEFs, the addition of antimycin A reduces the LC3-II levels and inhibits autophagy. Complex III regulates the activity of HIF1A, which regulates the expression of BNIP3, a mammalian mitophagy receptor, and promotes autophagy. In S. cerevisiae cells, the exogenous complex III inhibitor antimycin A or KCN induces autophagy, and the increased level of reduced cytochrome b may be the first signaling molecule in this pathway.