The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis

Carrat, Gaëlle; Haythorne, Elizabeth; Tomás, Alejandra; Haataja, Leena; Müller, Andreas; Arvan, Peter; Piunti, Alexandra; Cheng, Kaiying; Huang, Mutian; Pullen, Timothy J.; Georgiadou, Eleni; Stylianides, Theodoros; Amirruddin, Nur Shabrina; Salem, Victoria; Distaso, Walter; Cakebread, Andrew; Heesom, Kate J; Lewis, Philip A.; Hodson, David J.; Briant, Linford J.B.; Fung, Annie; Sessions, Richard B.; Alpy, Fabien; Kong, Alice Pik‐Shan; Benke, Peter I.; Torta, Federico; Teo, Adrian Kee Keong; Leclerc, Isabelle; Solimena, Michele; Wigley, Dale B.; Rutter, Guy A.

doi:10.1016/j.molmet.2020.101015

Cited by 24 publications

(14 citation statements)

References 81 publications

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“…100 μg aliquots of isolated mitochondria were digested with trypsin (40:1 protein:protease ratio) overnight at 37°C and labelled using the Tandem Mass Tag (TMT) 10-plex reagent, according to the manufacturer's instructions (Thermo Fisher Scientific, Loughborough, UK), and the labelled samples were pooled. Sample handling and fractionation by high pH reversed-phase chromatography was carried out as previously described ( Carrat et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

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Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health

Knapp-Wilson

Pereira

Buzzard

et al. 2021

Journal of Cell Science

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Mitochondrial super-complexes form around a conserved core of monomeric complex I and dimeric complex III; wherein subunit NDUFA11, of the former, is conspicuously situated at the interface. We identified B0491.5 (NDUF-11) as the C. elegans homologue, of which animals homozygous for a CRISPR-Cas9 generated knockout allele arrested at the L2 development stage. Reducing (but not eliminating) expression by RNAi allowed development to adulthood, enabling characterisation of the consequences: destabilisation of complex I and its super-complexes, and perturbation of respiratory function. The loss of NADH-dehydrogenase activity is compensated by enhanced complex II activity, with the potential for detrimental ROS-production. Electron cryo-tomography highlight aberrant cristae morphology and inter-membrane-space widening and cristae-junctions. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development presumably arises due to its involvement in complex I/ super-complex maintenance. This highlights the importance of respiratory complex integrity for health and the potential of its perturbation for mitochondrial disease.

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Section: Methodsmentioning

confidence: 99%

“…High pH reverse-phase fractions were further fractionated using an Ultimate 3000 nano-LC system in line with an Orbitrap Fusion Tribrid Mass Spectrometer (Thermo Scientific), as previously described ( Carrat et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health

Knapp-Wilson

Pereira

Buzzard

et al. 2021

Journal of Cell Science

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“…Although the molecular roles for STARD10 in the b cell remain to be elucidated, our recent findings (Carrat et al, 2020) indicate a role in the control of secretory granule biogenesis. Analysis of human islet pcHiC (Miguel-Escalada et al, 2019) and measurements of changes in gene expression after deletion of R2 region or the core of the VR provide evidence that FCHSD2 may also play a role in mediating disease risk.…”

Section: Discussionmentioning

confidence: 89%

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion

Cebola

Carrat

et al. 2021

Cell Reports

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“…High pH RP fractions were further fractionated using an Ultimate 3000 nano-LC system in line with an Orbitrap Fusion Tribrid Mass Spectrometer (Thermo Scientific), as previously described [72].…”

Section: Nano-lc Mass Spectrometrymentioning

confidence: 99%

“…TMT labelling and high pH reversed-phase chromatography 100 μg aliquots of isolated mitochondria were digested with trypsin (40:1 protein:protease ratio) overnight at 37 °C and labelled using the Tandem Mass Tag (TMT) 10-plex reagent, according to the manufacturer (Thermo Fisher Scientific, Loughborough LE11 5RG, UK), and the labelled samples were pooled. Sample handling and fractionation by high pH reversed-phase chromatography was carried as previously described [72].…”

mentioning

confidence: 99%

Maintenance of Complex I and respiratory super-complexes by NDUF-11 is essential for respiratory function, mitochondrial structure and health inC. elegans

Knapp-Wilson

Pereira

Buzzard

et al. 2021

Preprint

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Mitochondrial super-complexes form around a conserved core of monomeric complex I and dimeric complex III; wherein subunit NDUFA11, of the former, is conspicuously situated at the interface. We identified B0491.5 (NDUF-11) as the C. elegans homologue, of which animals homozygous for a CRISPR-Cas9 generated knockout allele arrested at the L2 development stage. Reducing expression by RNAi allowed development to the adult stage, enabling characterisation of the consequences: destabilisation of complex I and its super-complexes, and perturbation of respiratory function. The loss of NADH-dehydrogenase activity is compensated by enhanced complex II activity, resulting in excessive detrimental ROS production. Meanwhile, electron cryo-tomography highlight aberrant cristae morphology and widening of the inter-membrane space and cristae junctions. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development highlights the importance of complex I/ super-complex maintenance. Their perturbation by this, or other means, is likely to be the cause of metabolic stress and disease.

show abstract

The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis

Cited by 24 publications

References 81 publications

Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health

Maintenance of complex I and its supercomplexes by NDUF-11 is essential for mitochondrial structure, function and health

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion

Maintenance of Complex I and respiratory super-complexes by NDUF-11 is essential for respiratory function, mitochondrial structure and health inC. elegans

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