Research

将创作的自由还给创作者！爱发电是让创作者简单地获得稳定收入的粉丝赞助平台。无论你在创作什么，都能在这里获得持续的资金支持，让创作从此更自由。

将创作的自由还给创作者！爱发电是让创作者简单地获得稳定收入的粉丝赞助平台。无论你在创作什么，都能在这里获得持续的资金支持，让创作从此更自由。

将创作的自由还给创作者！爱发电是让创作者简单地获得稳定收入的粉丝赞助平台。无论你在创作什么，都能在这里获得持续的资金支持，让创作从此更自由。

将创作的自由还给创作者！爱发电是让创作者简单地获得稳定收入的粉丝赞助平台。无论你在创作什么，都能在这里获得持续的资金支持，让创作从此更自由。

将创作的自由还给创作者！爱发电是让创作者简单地获得稳定收入的粉丝赞助平台。无论你在创作什么，都能在这里获得持续的资金支持，让创作从此更自由。

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that plays a central role in Parkin-dependent mitophagy. Mutations in PINK1 are associated with autosomal recessive forms of Parkinson’s disease. PINK1 is identified as a high-affinity client of the HSP90–CDC37 complex. Stability of PINK1 is regulated by the HSP90–CDC37 chaperone system. However, the molecular mechanism by which HSP90– CDC37 recognizes and facilitate the folding of PINK1 remains unclear. Here, we present a cryogenic electron microscopy (cryo-EM) structure of the human PINK1–HSP90–CDC37 complex. The β5 strand of the PINK1 N-lobe projects into the central channel formed at the interface between two protomers in the HSP90 dimer, which holds the PINK1 kinase domain in a partially unfolded state. The C-lobe and unique C-terminal extension (CTE) of PINK1 is folded. HSP90 covers the CTE of PINK1, which overlaps with interaction sites for TOM5, TOM20, and the intramolecular N-helix. The HPNI motif of CDC37 interacts with the C-lobe of PINK1, mimicking the HPNI motif in the N-lobe of PINK1. A pathogenic mutation L347P is suggested to disrupt the interaction with the HPNI motif of CDC37. Another pathogenic mutation H271Q is located within the HPNI motif of the N-lobe of PINK1. These findings provide structural insights into the folding of PINK1 and its dysfunction in Parkinson’s disease. ### Competing Interest Statement The authors have declared no competing interest. Japan Society for the Promotion of Science, 21K15084, 24H01894, 18H05501

Waters et al. show that activation of the PINK1/Parkin mitophagy circuit is regulated by a PINK1 input threshold and an input-reciprocal circuit activation delay. The two regulatory behaviors emerge from the positive feedback architecture of the circuit. These findings suggest a mechanism by which cells can avoid errant mitochondrial degradation.

The protein kinase PINK1 is implicated in Parkinson’s disease and regulated by the heat shock protein Hsp90. Here, the authors obtain three cryo-EM structures of PINK1– Hsp90 complexes with different cochaperones and propose a regulatory mechanism.

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Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson's disease (PD). Consistent with this concept, loss of function mutations ...

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Mechanisms that prevent accidental activation of the PINK1/Parkin mitophagy circuit on healthy mitochondria are poorly understood. On the surface of d…

Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson’s disease cases. These genes encode the E3 ubiquitin li...

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Protein & Cell -

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The Parkinson’s disease linked kinase, PINK1, is a short lived protein that undergoes cleavage upon mitochondrial import leading to its release to the cytosol and proteasomal degradation. Under mitochondria depolarising conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Here we have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1 (cPINK1) in a cell line that lacks Parkin. We show that cPINK1 phosphorylates free ubiquitin and can be released to the cytosol in an active form. We show that in RPE1 cells under mitochondria depolarising conditions (i) the majority of PINK1 cleavage proceeds unimpeded and (ii) accrued PINK1 cannot be accounted for by protein stabilisation alone. Accordingly, we suggest that translation of PINK1 mRNA must be mobilised under mitochondrial depolarisation. We have further discovered a pre-conditioning phenomenon, whereby an initial depolarising treatment leaves a residual pool of active PINK1, which remains competent for seeding the activation of nascent cPINK1, despite a 16 hour recuperation period. ### Competing Interest Statement The authors have declared no competing interest.

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Mitophagy is crucial for mitochondrial quality control and maintenance of cellular homeostasis. Here the authors identify an E3 ubiquitin ligase, HUWE1, that collaborates with LC3-interacting protein AMBRA1 to induce mitochondrial clearance.

Mutations in parkin and phosphatase and tensin homolog–induced putative kinase 1 (PINK1) are individually associated with recessive familial forms of Parkinson disease (PD). Parkin is an E3 ligase that promotes ubiquitination of a number of substrates, including itself. In Drosophila, parkin plays...