Parkin-mediated selective mitochondrial autophagy, mitophagy: Parkin purges damaged organelles from the vital mitochondrial network - PubMed (original) (raw)

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Parkin-mediated selective mitochondrial autophagy, mitophagy: Parkin purges damaged organelles from the vital mitochondrial network

Atsushi Tanaka. FEBS Lett. 2010.

Abstract

Cellular homeostasis is linked tightly to mitochondrial functions. Some damage to mitochondrial proteins and nucleic acids can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. Mitochondrial dysfunction is one of the key aspects of the pathobiology of neurodegenerative disease. Parkin, an E3 ligase located in the cytosol and originally discovered as mutated in monogenic forms of Parkinson's disease (PD), was found recently to translocate specifically to uncoupled mitochondria and to induce their autophagy.

Published by Elsevier B.V.

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Figures

Fig 1. Mitochondria suffer cellular stress and require the maintenance systems

Many stress generated from inner (mtDNA mutations, deletions) or outer (oxidative stress, toxins) of mitochondria damage mitochondrial functions. If mitochondria failed to maintain their functions by their maintenance system, mitochondria proceed to dysfunctional state. Accumulation of dysfunctions, mitochondria should be eliminated by autophagy system, named mitophagy.

Fig 2. Parkin selectively translocates to the depolarized mitochondria

(a) Under normal conditions (left), most of the Parkin (green) is in cytosol, whereas some (arrows) are found on the fragmented mitochondria (red). When mitochondria were depolarized by CCCP (right), the cytoplasmic Parkin accumulated on the fragmented mitochondria. HEK293T cells, Scale: 5 μm. (b) In HeLa cells expressing YFP-Parkin, Parkin also accumulated on depolarized and fragmented mitochondria after CCCP treatment (right). Scale: 1 μm. (c) Only mitochondrial fragmentation by vMIA expression, whereas mitochondria maintain their membrane potential, does not signal for the Parkin translocation (left). Mitochondria blocked their division by Drp1K38A recruit YFP-Parkin upon depolarization (right). HeLa cells, Scale: 1 μm. (d) Mitochondria in MEF cells derived from Mfn1−/−, Mfn2−/−[53] mice, which are showing heterogenic mitochondrial membrane potential. Cytochrome c immunostaining indicates total mitochondrial images in a cell, Mitotracker Red indicates polarized (healthy, arrowhead) mitochondria. YFP-parkin accumulates only on depolarized (Mitotracker red-negative, damaged) mitochondria (arrows).

Fig 3. Parkin eliminates damaged mitochondria

(a) 1 hour after mitochondrial depolarization with CCCP, mitochondria (right) are surrounded by Parkin (center) and autophagosomes (LC3, left). (b) The recruitment of autophagosomes to mitochondria is induced by Parkin. In the absence of Parkin expression (left), depolarized mitochondria (red) are not associated with autophagosomes (LC3, green), whereas autophagosomes are more associated with mitochondria in the presence of Parkin (right). Scale: 1 μm. (c) 48 hours after mitochondrial depolarization with CCCP, mitochondria are not detectable with immunostaining. Only cells expressing YFP-Parkin (left), mitochondria (right) are completely eliminated. (d) 48 hours after mitochondrial depolarization with CCCP, mitochondria were taken up by lysosomes only in the HeLa cells expressing YFP-Parkin (right). Scale: 500 nm.

Fig 4. Working model for the Parkin-mediated mitochondrial quality control

Depolarized mitochondria are sensed by Parkin. After Parkin recruitment to the damaged mitochondria (PINK1 dependent), Parkin may ubiquitinate some substrates to degrade or tagging to proceed following process. After translocation, Parkin also recruits autophagosomes to promote mitophagy.

Fig 5. Working model for the Pathogenesis of PD

The vital mitochondrial network is maintained by the quality control (QC) system (top, also see in Figure 1). In pathological states of PD, cellular stress or damage cause the excess of damaged mitochondria, then overwhelm the QC system (middle). Disruption of mitochondrial QC system also accumulates damaged mitochondria (bottom). Both pathological states may cause the collapse of the cellular environment following by the cell death.

References

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Parkin-mediated selective mitochondrial autophagy, mitophagy: Parkin purges damaged organelles from the vital mitochondrial network - PubMed (original) (raw)