Dynamic tubulation of mitochondria drives mitochondrial network formation

Wang, Chong; Du, Wanqing; Su, Qian; Zhu, Maguang; Feng, Peiyuan; Liu, Ying; Zhou, Yisu; Mi, Na; Zhu, Yueyao; Jiang, Dong; Zhang, Senyan; Zhang, Zerui; Sun, Yujie; Yu, Li

doi:10.1038/cr.2015.89

Cited by 116 publications

(148 citation statements)

References 19 publications

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“…The fragmentation of mitochondria we observed in MiroS156E could, for example, reflect the secondary loss of proteins that support fusion (39,41,54), although it might also be because of the loss of kinesin from mitochondria when Miro is degraded (55). However, MiroS156E recruitment of Parkin did not induce detectable mitophagy, at least in the time frame that we analyzed (Fig.…”

Section: Discussionmentioning

confidence: 66%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

119

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The PTEN-induced putative kinase 1 (PINK1)/Parkin pathway can tag damaged mitochondria and trigger their degradation by mitophagy. Before the onset of mitophagy, the pathway blocks mitochondrial motility by causing Miro degradation. PINK1 activates Parkin by phosphorylating both Parkin and ubiquitin. PINK1, however, has other mitochondrial substrates, including Miro (also called RhoT1 and -2), although the significance of those substrates is less clear. We show that mimicking PINK1 phosphorylation of Miro on S156 promoted the interaction of Parkin with Miro, stimulated Miro ubiquitination and degradation, recruited Parkin to the mitochondria, and via Parkin arrested axonal transport of mitochondria. Although Miro S156E promoted Parkin recruitment it was insufficient to trigger mitophagy in the absence of broader PINK1 action. In contrast, mimicking phosphorylation of Miro on T298/T299 inhibited PINK1-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent mitochondrial arrest. The effects of the T298E/T299E phosphomimetic were dominant over S156E substitution. We propose that the status of Miro phosphorylation influences the decision to undergo Parkin-dependent mitochondrial arrest, which, in the context of PINK1 action on other substrates, can restrict mitochondrial dynamics before mitophagy.is the second most common neurodegenerative disorder, and is closely linked to mitochondrial dysfunction (1, 2). Two hereditary forms of recessive PD are caused by mutations in PINK1 (PTEN-induced putative kinase 1), a Ser/Thr mitochondrial kinase, and Parkin, a cytosolic E3 ubiquitin ligase (3, 4). The realization that these proteins are in a single pathway, with PINK1 acting upstream of Parkin to influence mitochondrial properties, was a critical step in uncovering the underlying pathological mechanisms of PD (5-7). This pathway can trigger the selective autophagy of damaged mitochondria, termed mitophagy (8, 9), but additional cellular functions have also been indicated for PINK1 and Parkin (10-15). Much, however, remains unclear about how the PINK1/Parkin pathway is regulated.In current models of PINK1/Parkin mitophagy (reviewed in ref. 1), healthy mitochondria import a PINK1 precursor constitutively to the inner membrane, where it is cleaved (16-18). The cleaved form then returns to the cytoplasm and is degraded by the N-end rule pathway (19). Mitochondrial depolarization, or protein misfolding in the matrix of energized mitochondria (20), prevent the import and degradation of PINK1, resulting in the accumulation of PINK1 on the outer mitochondrial membrane (OMM) (9,21,22). Once on the OMM, PINK1 kinase activity recruits Parkin from the cytosol (8, 9). Although Parkin adopts a self-inhibited conformation in solution (23-25), it becomes fully activated in a PINK1-dependent manner on the mitochondria (9, 21). Parkin ubiquitinates numerous proteins of the OMM (26, 27), and thereby recruits autophagy-related proteins to the damaged mitochondrion for autophagosome assembly (28-30).How PINK1 recruits and activa...

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Section: Discussionmentioning

confidence: 66%

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Shlevkov

Kramer

Schapansky

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

131

119

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“…The kinesin-family 5b (Kif5B) localizes to mitochondria in vivo and transport of mitochondria can be reconstituted in vitro on stabilized microtubules by adding recombinant purified Kif5B. Thus, kinesin can generate forces to transport mitochondria [23].…”

Section: The Mitochondrial Transport Machinerymentioning

confidence: 99%

Dynamics of the mitochondrial network during mitosis

Kanfer

Kornmann

2016

Biochemical Society Transactions

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During mitosis, cells undergo massive deformation and reorganization, impacting on all cellular structures. Mitochondria, in particular, are highly dynamic organelles, which constantly undergo events of fission, fusion and cytoskeleton-based transport. This plasticity ensures the proper distribution of the metabolism, and the proper inheritance of functional organelles. During cell cycle, mitochondria undergo dramatic changes in distribution. In this review, we focus on the dynamic events that target mitochondria during mitosis. We describe how the cell-cycle-dependent microtubule-associated protein centromeric protein F (Cenp-F) is recruited to mitochondria by the mitochondrial Rho GTPase (Miro) to promote mitochondrial transport and re-distribution following cell division.

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“…To examine the effects of Ca 2+ on the association of CaM with the MD-IQ1, we performed a pull- Single-Molecule Microscopy. The coverslips were cleaned by sonication and stored in double-distilled H 2 O to keep the surface hydrophilic (39). The flow chambers (25 × 0.2 × 2-3 mm, volume of 10-15 μL) used for the in vitro single-molecule assays were assembled as previously described (40).…”

Section: Methodsmentioning

confidence: 99%

Calmodulin in complex with the first IQ motif of myosin-5a functions as an intact calcium sensor

Shen

Zhang

Zheng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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The motor function of vertebrate myosin-5a is inhibited by its tail in a Ca 2+ -dependent manner. We previously demonstrated that the calmodulin (CaM) bound to the first isoleucine-glutamine (IQ) motif (IQ1) of myosin-5a is responsible for the Ca 2+ -dependent regulation of myosin-5a. We have solved the crystal structure of a truncated myosin-5a containing the motor domain and IQ1 (MD-IQ1) complexed with Ca

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Dynamic tubulation of mitochondria drives mitochondrial network formation

Cited by 116 publications

References 19 publications

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility

Dynamics of the mitochondrial network during mitosis

Calmodulin in complex with the first IQ motif of myosin-5a functions as an intact calcium sensor

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