The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation - PubMed (original) (raw)

Review

The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation

Koji Yamano et al. EMBO Rep. 2016 Mar.

Abstract

The quality of mitochondria, essential organelles that produce ATP and regulate numerous metabolic pathways, must be strictly monitored to maintain cell homeostasis. The loss of mitochondrial quality control systems is acknowledged as a determinant for many types of neurodegenerative diseases including Parkinson's disease (PD). The two gene products mutated in the autosomal recessive forms of familial early-onset PD, Parkin and PINK1, have been identified as essential proteins in the clearance of damaged mitochondria via an autophagic pathway termed mitophagy. Recently, significant progress has been made in understanding how the mitochondrial serine/threonine kinase PINK1 and the E3 ligase Parkin work together through a novel stepwise cascade to identify and eliminate damaged mitochondria, a process that relies on the orchestrated crosstalk between ubiquitin/phosphorylation signaling and autophagy. In this review, we highlight our current understanding of the detailed molecular mechanisms governing Parkin-/PINK1-mediated mitophagy and the evidences connecting Parkin/PINK1 function and mitochondrial clearance in neurons.

Keywords: PINK1; Parkin; Parkinson's disease; mitochondria; mitophagy.

© 2016 The Authors.

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Figures

Figure 1

Figure 1. PINK1 accumulation in the outer membrane of the damaged mitochondria

The newly synthesized

PINK

1 precursor is targeted to the damaged mitochondria. Because of the loss of membrane potential, the

PINK

1 precursor is not allowed to enter the inner membrane via the

TIM

23 complex. Instead, the

PINK

1 precursor is inserted into the outer membrane through the

TOM

complex in a

TOMM

7‐dependent manner.

PINK

1 stabilized on the outer membrane then forms a large complex with the

TOM

complex and undergoes intermolecular autophosphorylation at residues S228 and S402. 5, 6, 7, 20, 22, 40, and 70 denote

TOMM

5,

TOMM

6,

TOMM

7,

TOMM

20,

TOMM

22,

TOMM

40, and

TOMM

70, respectively.

Figure 2

Figure 2. Positive feedback ubiquitination cycles induced by Parkin and ubiquitin chain formation on damaged mitochondria

Although most of the ubiquitin diffuses in the cytosol, a fraction should reside on the outer membrane of healthy mitochondria since the ubiquitin system also contributes to the turnover of mitochondrial proteins under normal conditions 178 (Step 1). Following dissipation of the membrane potential,

PINK

1 is stabilized on the damaged mitochondria (Step 2).

PINK

1 can then phosphorylate the ubiquitin that is conjugated to the mitochondrial proteins, or

PINK

1 may also phosphory‐late Ser65 of cytosolic Parkin (Step 3). Of note, phosphorylated ubiquitin stably stays on the mitochondria because hydrolysis of phosphorylated ubiquitin chain by

DUB

s is impaired 75. Through higher affinity with phosphorylated ubiquitin, cytosolic Parkin is recruited to and retained on the mitochondria (Step 4).

PINK

1 further phosphorylates Parkin on the mitochondria.

PINK

1 may also phosphorylate Ser65 of cytosolic ubiquitin (Step 5). The fully activated, phosphorylated Parkin can then elongate ubiquitin chains or generate a new ubiquitinated substrate from cytosolic‐free ubiquitin. In other words, cytosolic ubiquitin is recruited to the mitochon‐dria through a ubiquitination reaction by activated Parkin (Step 6). The ubiquitin on the mitochondrial substrate is phosphorylated by

PINK

1 (Step 7 is the next round of the Step 3). Positive feedback amplification cycles (Steps 3–7) result in both Parkin and ubiquitin recruitment to and poly‐ubiquitin chain formation on the damaged mitochondria (Step 8).

Figure 3

Figure 3. Ephemeral life of PINK1 in the healthy mitochondria

(A) The newly synthesized

PINK

1 precursor on the cytosolic ribosomes is targeted to the mitochondria. After crossing the outer membrane through the

TOM

complex, the N‐terminal mitochondrial targeting sequence is cleaved by

MPP

in the matrix. The following transmembrane segment is recognized by the

TIM

23 complex and received second cleavage by

PARL

between A103 and F104. Most of the cleaved

PINK

1 is released to the cytosol where the newly N‐terminal phenylalanine residue of the cleaved

PINK

1 is recognized by the N‐end rule

UBR

ligases (

UBR

1,

UBR

2, and

UBR

4 that preferentially recognize type‐2 N‐degrons) for proteasomal degradation. A matrix

ATP

ase associated with diverse cellular activities (m‐

AAA

) protease is composed of

AFG

3L2 and paraplegin and has the active site oriented toward the matrix. Clp

XP

is a matrix

ATP

‐dependent protease composed of hetero‐oligomeric

ATP

‐binding subunits and proteolytic subunits. m‐

AAA

and Clp

XP

also participate in

PINK

1 degradation. Another

ATP

‐dependent

LON

protease also contributes, particularly in Drosophila, to

PINK

1 degradation in the matrix. As phosphorylation of

NDUFA

10 in the respiratory chain complex I is reduced in _Pink1_‐

KO

mice, a small amount of

PINK

1 retained in the inner membrane might be involved in the maintenance of complex I through phosphorylation. (B) Amino acid sequence alignment of the transmembrane region of

PINK

1. Amino acid sequences of the predicted transmembrane segments (pink‐colored box) from the indicated species are shown 99. The transmembrane regions are well conserved from zebrafish (Danio rerio) and humans (Homo sapiens), while the transmembrane segment in fly (Drosophila melanogaster) is less conserved with fewer glycine/proline residues. The

PARL

cleavage site of human

PINK

1 between A103 and F104 is also shown.

Figure 4

Figure 4. Activation and recruitment of autophagy machineries during Parkin‐/PINK1‐mediated mitophagy

Following the generation of poly‐ubiquitin chains on damaged mitochondria, the indicated autophagy proteins including adaptors and regulators are recruited to the mitochondria in a multi‐independent process. (i) While autophagosomes form at

ER

–mitochondria contact sites under starvation‐induced autophagy 179, how the

ULK

1 and

PI

3K complexes and the omegasome marked by

DFCP

1 recognize mitochondrial damage remains unknown. (ii) Poly‐ubiquitin chains on the mitochondria are directly recognized by the autophagy adaptors, in particular

NDP

52 and optineurin (

OPTN

), which are phosphorylated by

TBK

1, and promote the recruitment of the

LC

3‐labeled isolation membrane. (iii) Atg9A vesicles are independently recruited to the mitochondria through an unknown mechanism. (iv) Mitochondria‐localized Rab‐

GAP

s,

TBC

1D15 and

TBC

1D17, via interaction of Fis1 regulate proper autophagosomal formation by modulating Rab7 activity. (v) Upon mitophagy stimulation, a regulator of autophagy‐lysosome biogenesis,

TFEB

(as well as

MITF

and

TFE

3), is activated in an Atg5‐ and Atg9A‐dependent manner.

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