Tom70 Is Essential for PINK1 Import into Mitochondria

Kato, Hiromichi; Lu, Qiping; Rapaport, Doron; Kozjak-Pavlovic, Vera

doi:10.1371/journal.pone.0058435

Cited by 55 publications

(61 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two evolutionarily conserved autophosphorylation sites within the kinase domain have been shown to promote parkin recruitment to depolarized mitochondria. also support the prediction that conserved regions of PINK1 at residues 8-18 and 67-77 contain potential MPP cleavage motifs (97), although the involvement of MPP has been controversial (6,55). AFG3L2 (m-AAA catalytic subunit) has been suggested as the protease producing the DN 2 fragment (*45 kDa band) (39,100).…”

Section: Structure and Processing Of Pink1supporting

confidence: 65%

See 1 more Smart Citation

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Steer

Dail

Chu

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Disruptions in mitochondrial homeostasis are implicated in human diseases across the lifespan. Recessive mutations in PINK1, which encodes the mitochondrially targeted PTEN-induced putative kinase 1 (PINK1), cause an autosomal recessive form of Parkinson's disease. As with all kinases, PINK1 participates in multiple functional pathways, and its dysregulation has been implicated in a growing number of diseases. Recent Advances: In addition to its heavily studied role in mitophagy, PINK1 regulates mitochondrial respiratory function, reactive oxygen species generation, and mitochondrial transport. Moreover, recent studies implicate processed PINK1 in cytosolic signaling cascades that promote cell survival and neuron differentiation. Cytosolic PINK1 is also capable of suppressing autophagy and mitophagy. We propose a working hypothesis that PINK1 is released by functional mitochondria as a signal to coordinate cell growth and differentiation in response to mitochondrial status. Critical Issues: PINK1 biology needs to be better understood in primary neurons, as the stability and subcellular localization of PINK1 is differentially regulated in different cell types. Delineating factors that regulate its mitochondrial import/export, processing by different peptidases, kinase activity, subcellular localization, and degradation will be important for defining relevant downstream kinase targets. Future Directions: It is becoming clear that different subcellular pools of PINK1 mediate distinct functions. Future studies will undoubtedly expand on the spectrum of cellular functions regulated by PINK1. Continued study of cytosolic PINK1 may offer novel insights into how functional mitochondria communicate their status with the rest of the cell. Antioxid. Redox Signal. 22, 1047-1059. P arkinson's disease (PD) is a debilitating age-related neurodegenerative disorder that affects 4-5 million people in the world's most populous nations (28). PD pathology is characterized by: (i) Lewy body inclusions, which contain alpha-synuclein and ubiquitin, in autonomic, brainstem and cortical regions (10), and (ii) the loss of pigmented brain stem neurons from the substantia nigra and locus ceruleus. Degeneration of dopaminergic nigral neurons account for the classic motor signs, although other neuron groups are also affected. While the majority of PD cases are idiopathic, studies of gene products implicated in familial PD implicate common pathways that are likely to be important for disease progression (101).Mutations in PINK1, which encodes PTEN-induced putative kinase 1 (PINK1), represent the second most common cause of autosomal recessive parkinsonism (48,103). PINK1 families exhibit an earlier onset of disease (range of 9-52 years), accompanied by sustained responses to levodopa treatment (9,57,64,103). Autopsy findings have been reported from one family, showing classic Lewy body pathology (92). Pathways regulated by PINK1 appear to interact with other PD-linked genes (11,20,91), and PINK1 enhances the resistance of...

show abstract

Section: Structure and Processing Of Pink1supporting

confidence: 65%

“…2). An alternate pathway of PINK1 import that does not require TOM40 has also been described in a cell-free import system (55).…”

Section: Structure and Processing Of Pink1mentioning

confidence: 98%

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Steer

Dail

Chu

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…25 Despite that cytosolic retention, it is still a matter of debate how PINK1-66 associates with the outer membrane. [35][36][37] Here we show that PINK1-66 inserted into the inner membrane,…”

Section: Discussionmentioning

confidence: 62%

“…Cell-free mitochondrial import assays and BN-PAGE suggest that PINK1-66 does not accumulate in the proteinconducting channel formed by TOMM40, but creates a stable complex with the substrate receptor TOMM20. 35 However, more recent studies propose TOMM70 36 and TOMM7 37 to govern this noncanonical outer membrane insertion route. Despite that controversy, a putative role of a substrate receptor in the outer membrane insertion pathway is consistent with our observation that PINK1-66 trapped by the PARL S275A mutant at the inner membrane blocks CCCP-mediated PARK2 translocation by newly synthesized PINK1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

et al. 2015

View full text Add to dashboard Cite

Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients.

show abstract

“…Recent reports describe that Tom70 is essential for Pink1 translocation to mitochondria [29], and Pink1 is required for mitophagy and subsequently ROS production [30]. To elucidate whether Pink1 was also involved in the development of cardiac hypertrophy caused by Tom70 reduction, we conducted knockdown experiments using Pink1 siRNA in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

Liu

et al. 2014

Cell Res

View full text Add to dashboard Cite

Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy. Keywords: pathological cardiac hypertrophy; translocases of mitochondrial outer membrane; optic atrophy-1; oxidative stress Cell Research (2014) 24:977-993.

show abstract

Tom70 Is Essential for PINK1 Import into Mitochondria

Cited by 55 publications

References 33 publications

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Beyond Mitophagy: Cytosolic PINK1 as a Messenger of Mitochondrial Health

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

Contact Info

Product

Resources

About