Mitochondrial Genome Maintenance 1 (Mgm1) Protein Alters Membrane Topology and Promotes Local Membrane Bending

Rujiviphat, Jarungjit; Wong, Michael K.; Won, Amy; Shih, Yu‐Ling; Yip, Christopher M.; McQuibban, G. Angus

doi:10.1016/j.jmb.2015.03.006

Cited by 27 publications

(13 citation statements)

References 37 publications

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“…Very interestingly, recent experiments with reconstituted vesicles have revealed that Mgm1 mediates membrane bending (Rujiviphat et al, 2015). Bending of crista membranes takes place only when the F 1 F O -ATP synthase can dimerize (Davies et al, 2012; Rabl et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

Harner

Unger

Geerts

et al. 2016

eLife

115

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Metabolic function and architecture of mitochondria are intimately linked. More than 60 years ago, cristae were discovered as characteristic elements of mitochondria that harbor the protein complexes of oxidative phosphorylation, but how cristae are formed, remained an open question. Here we present experimental results obtained with yeast that support a novel hypothesis on the existence of two molecular pathways that lead to the generation of lamellar and tubular cristae. Formation of lamellar cristae depends on the mitochondrial fusion machinery through a pathway that is required also for homeostasis of mitochondria and mitochondrial DNA. Tubular cristae are formed via invaginations of the inner boundary membrane by a pathway independent of the fusion machinery. Dimerization of the F1FO-ATP synthase and the presence of the MICOS complex are necessary for both pathways. The proposed hypothesis is suggested to apply also to higher eukaryotes, since the key components are conserved in structure and function throughout evolution.DOI: http://dx.doi.org/10.7554/eLife.18853.001

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Section: Resultsmentioning

confidence: 99%

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

Harner

Unger

Geerts

et al. 2016

eLife

115

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“…Deletion of OPA1 not only causes mitochondrial fragmentation, which is evidently linked to its fusion activity, but also diminishes cristae biogenesis, in that IMM becomes vesicular, as observed by EM [78]. Purified short Mgm1 (s-Mgm1) and short OPA1 (s-OPA1) are able to interact with IMM-like liposomes, induce local membrane bending, and deform them into tubule-like structures [86,87]. Tubulation of membranes by these DLPs is consistent with the formation of IMM protrusions between cristae.…”

Section: Opa1 Structures and Mitochondrial Inner Membrane Fusionmentioning

confidence: 98%

Mitochondrial Fusion: The Machineries In and Out

Gao

2021

Trends in Cell Biology

240

147

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Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several human diseases. The fusion of the outer (OMM) and inner mitochondrial membranes (IMM) is mediated by two classes of dynamin-like protein (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information on these fusogens, the molecular mechanisms underlying mitochondrial fusion remain unclear, even after 20 years. Here, we review recent advances in structural studies of the mitochondrial fusion machinery, discuss their implication for DLPs, and summarize the pathogenic mechanisms of disease-causing mutations in mitochondrial fusion DLPs. The Mitochondrial Fusion MachineryMitochondria are double-membrane organelles that confer various essential cellular functions, including energy production, metabolism, apoptosis, and innate immunity [1]. They form a highly dynamic network and constantly undergo cycles of fusion and fission. The balance between fission and fusion has critical roles in maintaining mitochondrial homeostasis in response to metabolic or environmental stresses, and is linked to cell division, apoptosis, and autophagy [2-5]. In particular, fusion promotes the capacity of oxidative phosphorylation and allows redistribution of mitochondrial (mt)DNA between damaged and healthy mitochondria [6,7]. Disruptions of mitochondrial dynamics are implicated in aging as well as in several human diseases, including neurodegenerative and metabolic disorders, and cancer [8,9]. Mitochondrial fusion is a two-step process; fusion of the OMM is mediated by Fzo1 in yeast, Fzo (see Glossary) in flies, and MFN in mammals, whereas the IMM is fused by Mgm1 in yeast and OPA1 in mammals [10,11].MFN and Fzo1 were identified some 20 years ago [12][13][14][15]. Mammals have two MFNs, namely MFN1 and MFN2. Functionally, MFN1 and MFN2 share not only a certain amount of redundancy, but also substantial differences [15,16]. Mice with deletion of either MFN1 or MFN2 die in utero in mid-gestation [14]. MFN2 mutation accounts for most cases of Charcot-Marie-Tooth disease type 2A (CMT2A), a neuromuscular disorder [17]. The yeast IMM fusogen Mgm1 was initially identified as a key regulator of mtDNA maintenance [18,19]. The human OPA1 gene was mapped in genetic studies of patients with autosomal dominant optic atrophy (ADOA) [20], a hereditary neurodegenerative disease. Around the same time as the initial characterization of Fzo1 and MFNs, Mgm1 and OPA1 were annotated as membrane-bound GTPases and subsequently found to serve as IMM fusogens and cristae-shaping proteins [18,21,22]. Linkage of mitochondrial fusogen mutations to neurodegenerative diseases emphasizes the physiological importance of mitochondrial membrane dynamics in neuronal cells, likely explained by the high demand for energy there [4,8].The mechanism of mitochondrial fusion is unclear, partly due to the lack of structural in...

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“…In vitro assays indicate that mitochondrial fusion requires the heterooligomeric assembly of both forms of Mgm1 and depends on the GTPase activity of S-Mgm1, which facilitates L-Mgm1-mediated structural changes in the IMM (DeVay et al, 2009;Rujiviphat et al, 2015;Zick et al, 2009). Pcp1-deleted yeast strains are unable to generate S-Mgm1 and have a fragmented mitochondrial network with disordered cristae; they also lose mtDNA and have reduced respiratory competence (Herlan et al, 2003;McQuibban et al, 2003).…”

Section: Box 1 Processing Of Yeast Mgm1mentioning

confidence: 99%

OPA1 processing in cell death and disease – the long and short of it

MacVicar

Langer

2016

Journal of Cell Science

369

318

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The regulation of mitochondrial dynamics by the GTPase OPA1, which is located at the inner mitochondrial membrane, is crucial for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. As discussed in this Commentary, these morphological changes are regulated by proteolytic processing of OPA1 by the inner-membrane peptidases YME1L (also known as YME1L1) and OMA1. Long, membrane-bound forms of OPA1 are required for mitochondrial fusion, but their processing to short, soluble forms limits fusion and can facilitate mitochondrial fission. Excessive OPA1 processing by the stress-activated protease OMA1 promotes mitochondrial fragmentation and, if persistent, triggers cell death and tissue degeneration in vivo. The prevention of OMA1-mediated OPA1 processing and mitochondrial fragmentation might thus offer exciting therapeutic potential for human diseases associated with mitochondrial dysfunction.

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Mitochondrial Genome Maintenance 1 (Mgm1) Protein Alters Membrane Topology and Promotes Local Membrane Bending

Cited by 27 publications

References 37 publications

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

An evidence based hypothesis on the existence of two pathways of mitochondrial crista formation

Mitochondrial Fusion: The Machineries In and Out

OPA1 processing in cell death and disease – the long and short of it

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