WBSCR16 Is a Guanine Nucleotide Exchange Factor Important for Mitochondrial Fusion

Huang, Guohong; Massoudi, Dawiyat; Muir, Alison M.; Joshi, D. C.; Zhang, Chuan-Li; Chiu, Shing Yan; Greenspan, Daniel S.

doi:10.1016/j.celrep.2017.06.090

Cited by 18 publications

(20 citation statements)

References 44 publications

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“…To reconcile the difference in mouse and human ATP synthase dimerization, we searched the literature and came across a report that identified RCC1L as a guanine nucleotide exchange factor for OPA1, the known mitochondrial fusion protein (Cipolat et al, 2004; Huang et al, 2017). This report showed that decreased RCC1L can phenocopy mitochondrial defects observed in Opa1 knockout cells, which themselves can exhibit decreased ATP synthase dimers and dissociation of OXPHOS supercomplexes (Cogliati et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

Tebbenkamp

Varela

Choi

et al. 2018

Cell

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SUMMARY Despite the known causality of copy number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each genes’ contribution to the constellation of neural phenotypes remains elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with the decreased integrity of oxidative phosphorylation supercomplexes and ATP synthase dimers we observed in WS. Thus, we reveal DNAJC30 as a novel auxiliary component of ATP synthase machinery, and link mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

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Section: Resultsmentioning

confidence: 99%

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

Tebbenkamp

Varela

Choi

et al. 2018

Cell

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“…However, RCC1L V1 does not contain any RNA modifying domain and therefore its effect on 16S rRNA might be through the interaction with pseudouridylation proteins. There are two possible scenarios for this interaction: (i) RCC1L V1 directly regulates the steady-state levels and/or activity of pseudouridylation proteins by an unknown mechanism or (ii) most likely RCC1L V1 , through its GDP/GTP nucleotide exchange factor activity [ 22 ], regulates certain mtLSU GTPases that would act upon pseudouridylation proteins. Out of the three GTPases described to be involved in mtLSU biogenesis, MTG1, MTG2 and GTPBP10, our results pointed towards the latter as the most likely candidate.…”

Section: Discussionmentioning

confidence: 99%

“…This subgroup includes three additional members: RCC1, a GEF for the GTPase Ran [ 16 ], RCC2 (TD60), a deactivator of the GTPase Rac1 that switches its GTP for GDP [ 17 ] and DelGEF, a less characterized protein involved in regulating the GTP binding to one of the GTPases of the secretion Sec6/8 complex [ 18 ]. In mammals, RCC1L has been identified either as a component of the so called “mitochondrial pseudouridylation module”, a set of proteins involved in pseudouridylating 16S rRNA (TRUB2, RPUSD3, RPUSD4, NGRN, FASTKD2) and interacting with the mitoribosome mtLSU [ 19 ] [ 20 ] [ 21 ] [ 11 ] or as GEF for the mitochondrial fusion GTPase OPA1 [ 22 ]. However, very little attention has been paid to the fact that three different isoforms originated by alternative splicing have been identified for RCC1L, RCC1L V1-3 , all of them sharing the same N-terminus and, therefore, all three predicted to be mitochondrial [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

RCC1L (WBSCR16) isoforms coordinate mitochondrial ribosome assembly through their interaction with GTPases

et al. 2020

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Mitochondrial translation defects can be due to mutations affecting mitochondrial- or nuclear-encoded components. The number of known nuclear genes involved in mitochondrial translation has significantly increased in the past years. RCC1L (WBSCR16), a putative GDP/GTP exchange factor, has recently been described to interact with the mitochondrial large ribosomal subunit. In humans, three different RCC1L isoforms have been identified that originate from alternative splicing but share the same N-terminus, RCC1L V1 , RCC1L V2 and RCC1L V3 . All three isoforms were exclusively localized to mitochondria, interacted with its inner membrane and could associate with homopolymeric oligos to different extent. Mitochondrial immunoprecipitation experiments showed that RCC1L V1 and RCC1L V3 associated with the mitochondrial large and small ribosomal subunit, respectively, while no significant association was observed for RCC1L V2 . Overexpression and silencing of RCC1L V1 or RCC1L V3 led to mitoribosome biogenesis defects that resulted in decreased translation. Indeed, significant changes in steady-state levels and distribution on isokinetic sucrose gradients were detected not only for mitoribosome proteins but also for GTPases, (GTPBP10, ERAL1 and C4orf14), and pseudouridylation proteins, (TRUB2, RPUSD3 and RPUSD4). All in all, our data suggest that RCC1L is essential for mitochondrial function and that the coordination of at least two isoforms is essential for proper ribosomal assembly.

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“…Mice heterozygous for the mutation are shown to have neuronal mitochondria with reduced membrane potential and increased susceptibility to mitochondrial fragmentation in response to excitotoxic stress. Implications of the data are discussed [118] OPA…”

Section: Williams-beuren Syndrome Multigene Deletionmentioning

confidence: 99%

Mitochondrial Dynamics in Basal and Stressful Conditions

Zemirli

Morel

Molino

2018

IJMS

131

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The historical role of mitochondria resides in converting the energy released during the oxidation of macromolecules (carbohydrates, lipids and proteins) into adenosine tri-phosphate, a major form of chemically stored energy which sustains cell growth and homeostasis. Beyond this role in bioenergetics regulation, mitochondria play a role in several other cellular processes including lipid metabolism, cellular calcium homeostasis, autophagy and immune responses. Furthermore, mitochondria are highly dynamic organelles: as all other cellular endomembranes, they are continuously moving along cytoskeleton, and, most importantly, they constantly interact one with each other by membrane tethering, fusion and fission. This review aims to highlight the tight correlation between the morphodynamics of mitochondria and their biological function(s), in physiological as well as stress conditions, in particular nutrient deprivation, pathogen attack and some human diseases. Finally, we emphasize some crosstalk between the fusion/fission machinery and the autophagy pathway to ending on some speculative hypothesis to inspire future research in the field.

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WBSCR16 Is a Guanine Nucleotide Exchange Factor Important for Mitochondrial Fusion

Cited by 18 publications

References 44 publications

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development

RCC1L (WBSCR16) isoforms coordinate mitochondrial ribosome assembly through their interaction with GTPases

Mitochondrial Dynamics in Basal and Stressful Conditions

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