Structural analysis of a trimeric assembly of the mitochondrial dynamin-like GTPase Mgm1

Yan, Liming; Qi, Yuming; Ricketson, Derek; Li, Lei; Subramanian, Kelly; Zhao, Jingru; Yu, Chengbin; Wu, Lijun; RD, Sarsam; Wong, Melissa S.; Lou, Zhiyong; Rao, Zihe; Nunnari, Jodi; Hu, Junjie

doi:10.1073/pnas.1919116117

Cited by 46 publications

(53 citation statements)

References 59 publications

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“…Intriguingly, immediately before membrane fusion of the two organelles, we observed finger-like protrusions from the ends of one of the mitochondria (Figs 11A, S4A, and Videos 9 and 10), which appeared to bridge the membranes of the two organelles. This observation supports recently published models of Mgm1/Opa1-mediating IMM fusion through the formation of highly curved membrane tips (Yan et al, 2020). Using live-cell SIM imaging, we observed the formation of such IMM protrusions on one, rather than both, of the fusing mitochondria.…”

Section: Tws Protocol Can Quantify Acute Changes In Mitochondrial Ultsupporting

confidence: 91%

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria

et al. 2020

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Recent breakthroughs in live-cell imaging have enabled visualization of cristae, making it feasible to investigate the structure–function relationship of cristae in real time. However, quantifying live-cell images of cristae in an unbiased way remains challenging. Here, we present a novel, semi-automated approach to quantify cristae, using the machine-learning Trainable Weka Segmentation tool. Compared with standard techniques, our approach not only avoids the bias associated with manual thresholding but more efficiently segments cristae from Airyscan and structured illumination microscopy images. Using a cardiolipin-deficient cell line, as well as FCCP, we show that our approach is sufficiently sensitive to detect perturbations in cristae density, size, and shape. This approach, moreover, reveals that cristae are not uniformly distributed within the mitochondrion, and sites of mitochondrial fission are localized to areas of decreased cristae density. After a fusion event, individual cristae from the two mitochondria, at the site of fusion, merge into one object with distinct architectural values. Overall, our study shows that machine learning represents a compelling new strategy for quantifying cristae in living cells.

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Section: Tws Protocol Can Quantify Acute Changes In Mitochondrial Ultsupporting

confidence: 91%

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria

et al. 2020

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“…Membrane-anchored long forms of OPA1 (L-OPA1) undergo proteolytic cleavage at the S1 or S2 sites by a group of proteases residing in the mitochondrial intermembrane space (e.g., PARL, PRELI, Yme1L, and OMA1), resulting in soluble short forms of OPA1 (S-OPA1) (13,(56)(57)(58). Recently, crystal structures of short Mgm1p (S-Mgm1) from C. thermophilum (59) and S. cerevisiae (60), orthologs of S-OPA1, have been determined, providing a mechanistic platform for understanding the functions of Mgm1/OPA1 during mitochondrial inner membrane fusion. It has been suggested that both long and short forms of OPA1 are required for inner membrane fusion (57).…”

Section: The Mammalian Mitochondrial Fusion Machinerymentioning

confidence: 99%

Regulation of Mammalian Mitochondrial Dynamics: Opportunities and Challenges

et al. 2020

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Mitochondria are highly dynamic organelles and important for a variety of cellular functions. They constantly undergo fission and fusion events, referred to as mitochondrial dynamics, which affects the shape, size, and number of mitochondria in the cell, as well as mitochondrial subcellular transport, mitochondrial quality control (mitophagy), and programmed cell death (apoptosis). Dysfunctional mitochondrial dynamics is associated with various human diseases. Mitochondrial dynamics is mediated by a set of mitochondria-shaping proteins in both yeast and mammals. In this review, we describe recent insights into the potential molecular mechanisms underlying mitochondrial fusion and fission, particularly highlighting the coordinating roles of different mitochondria-shaping proteins in the processes, as well as the roles of the endoplasmic reticulum (ER), the actin cytoskeleton and membrane phospholipids in the regulation of mitochondrial dynamics. We particularly focus on emerging roles for the mammalian mitochondrial proteins Fis1, Mff, and MIEFs (MIEF1 and MIEF2) in regulating the recruitment of the cytosolic Drp1 to the surface of mitochondria and how these proteins, especially Fis1, mediate crosstalk between the mitochondrial fission and fusion machineries. In summary, this review provides novel insights into the molecular mechanisms of mammalian mitochondrial dynamics and the involvement of these mechanisms in apoptosis and autophagy.

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“…Mechanistic studies of ATL and MFN have demonstrated that nucleotidedependent dimerization of the G domain and movement of the HB domain relative to the G domain play critical roles in the fusion reaction. Recent structural studies of Mgm1 have revealed a similar configuration, in which the G domain is closely associated with an HB domain (Faelber et al, 2019;Yan et al, 2020). Chaetomium thermophilum Mgm1 has been visualized as a tetramer, similar to fission dynamins, the high-order assembly of which is proposed to remodel IMMs (Faelber et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into G domain dimerization and pathogenic mutation of OPA1

Zhao

Yan

et al. 2020

Journal of Cell Biology

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The fusion of mammalian inner mitochondrial membranes (IMMs) is mediated by dynamin-like GTPase OPA1. Mutations in human OPA1 cause optic atrophy, but the molecular basis for membrane fusion and pathogenesis is not clear. Here, we determined the crystal structure of the minimal GTPase domain (MGD) of human OPA1. A three-helix bundle (HB) domain including two helices extending from the GTPase (G) domain and the last helix of OPA1 tightly associates with the G domain. In the presence of GDP and BeF3−, OPA1-MGD forms a dimer, the interface of which is critical for the maintenance of mitochondrial morphology. The catalytic core of OPA1 possesses unique features that are not present in other dynamin-like proteins. Biochemical experiments revealed that OPA1-MGD forms nucleotide-dependent dimers, which is important for membrane-stimulated GTP hydrolysis, and an N-terminal extension mediates nucleotide-independent dimerization that facilitates efficient membrane association. Our results suggest a multifaceted assembly of OPA1 and explain the effect of most OPA1 mutations on optic atrophy.

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Structural analysis of a trimeric assembly of the mitochondrial dynamin-like GTPase Mgm1

Cited by 46 publications

References 59 publications

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria

Regulation of Mammalian Mitochondrial Dynamics: Opportunities and Challenges

Structural insights into G domain dimerization and pathogenic mutation of OPA1

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