Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+

Paola Venco; Massimo Bonora; Carlotta Giorgi; Elena Papaleo; Arcangela Iuso; Holger Prokisch; Paolo Pinton; Valeria Tiranti

doi:10.3389/fgene.2015.00185

Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺

Paola Venco, Massimo Bonora, Carlotta Giorgi, Elena Papaleo, Arcangela Iuso, Holger Prokisch, Paolo Pinton, Valeria Tiranti^*

^*Corresponding author for this work

Biomolecular Sciences

35 Citations (Scopus)

86 Downloads (Pure)

Abstract

Mutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation in the basal ganglia. By using western blot analysis with specific antibody and confocal studies, we showed that wild-type C19orf12 protein was not exclusively present in mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria Associated Membrane), while mutant C19orf12 variants presented a different localization. Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein was able to relocate to the cytosol. On the contrary, mutant isoforms were not able to respond to oxidative stress. High mitochondrial calcium concentration and increased H₂O₂ induced apoptosis were found in fibroblasts derived from one patient as compared to controls. C19orf12 protein is a 17 kDa mitochondrial membrane-associated protein whose function is still unknown. Our in silico investigation suggests that, the glycine zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and C-terminal regions with respect to the transmembrane portion, on the contrary, are predicted to rearrange in a structural domain, which is homologs to the N-terminal regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may act as a regulatory protein for human MgtE transporters. The mutations here described affect respectively one glycine residue of the glycine zipper motifs, which are involved in dimerization of transmembrane helices and predicted to impair the correct localization of the protein into the membranes, and one residue present in the regulatory domain, which is important for protein-protein interaction.

Original language	English
Article number	185
Journal	Frontiers in Genetics
Volume	6
Number of pages	14
ISSN	1664-8021
DOIs	https://doi.org/10.3389/fgene.2015.00185
Publication status	Published - 2015

Keywords

Endoplasmic reticulum-mitochondria associated membranes (ER-MAM)
Mitochondria
Molecular modeling
Neurodegeneration with brain iron accumulation
Oxidative stress
Simulation

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Venco, P., Bonora, M., Giorgi, C., Papaleo, E., Iuso, A., Prokisch, H., Pinton, P., & Tiranti, V. (2015). Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺. Frontiers in Genetics, 6, Article 185. https://doi.org/10.3389/fgene.2015.00185

Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺. / Venco, Paola; Bonora, Massimo; Giorgi, Carlotta et al.
In: Frontiers in Genetics, Vol. 6, 185, 2015.

Research output: Contribution to journal › Journal article › Research › peer-review

Venco, P, Bonora, M, Giorgi, C, Papaleo, E, Iuso, A, Prokisch, H, Pinton, P & Tiranti, V 2015, 'Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺', Frontiers in Genetics, vol. 6, 185. https://doi.org/10.3389/fgene.2015.00185

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abstract = "Mutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation in the basal ganglia. By using western blot analysis with specific antibody and confocal studies, we showed that wild-type C19orf12 protein was not exclusively present in mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria Associated Membrane), while mutant C19orf12 variants presented a different localization. Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein was able to relocate to the cytosol. On the contrary, mutant isoforms were not able to respond to oxidative stress. High mitochondrial calcium concentration and increased H2O2 induced apoptosis were found in fibroblasts derived from one patient as compared to controls. C19orf12 protein is a 17 kDa mitochondrial membrane-associated protein whose function is still unknown. Our in silico investigation suggests that, the glycine zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and C-terminal regions with respect to the transmembrane portion, on the contrary, are predicted to rearrange in a structural domain, which is homologs to the N-terminal regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may act as a regulatory protein for human MgtE transporters. The mutations here described affect respectively one glycine residue of the glycine zipper motifs, which are involved in dimerization of transmembrane helices and predicted to impair the correct localization of the protein into the membranes, and one residue present in the regulatory domain, which is important for protein-protein interaction.",

keywords = "Endoplasmic reticulum-mitochondria associated membranes (ER-MAM), Mitochondria, Molecular modeling, Neurodegeneration with brain iron accumulation, Oxidative stress, Simulation",

author = "Paola Venco and Massimo Bonora and Carlotta Giorgi and Elena Papaleo and Arcangela Iuso and Holger Prokisch and Paolo Pinton and Valeria Tiranti",

year = "2015",

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T1 - Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+

AU - Venco, Paola

AU - Bonora, Massimo

AU - Giorgi, Carlotta

AU - Papaleo, Elena

AU - Iuso, Arcangela

AU - Prokisch, Holger

AU - Pinton, Paolo

AU - Tiranti, Valeria

PY - 2015

Y1 - 2015

N2 - Mutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation in the basal ganglia. By using western blot analysis with specific antibody and confocal studies, we showed that wild-type C19orf12 protein was not exclusively present in mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria Associated Membrane), while mutant C19orf12 variants presented a different localization. Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein was able to relocate to the cytosol. On the contrary, mutant isoforms were not able to respond to oxidative stress. High mitochondrial calcium concentration and increased H2O2 induced apoptosis were found in fibroblasts derived from one patient as compared to controls. C19orf12 protein is a 17 kDa mitochondrial membrane-associated protein whose function is still unknown. Our in silico investigation suggests that, the glycine zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and C-terminal regions with respect to the transmembrane portion, on the contrary, are predicted to rearrange in a structural domain, which is homologs to the N-terminal regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may act as a regulatory protein for human MgtE transporters. The mutations here described affect respectively one glycine residue of the glycine zipper motifs, which are involved in dimerization of transmembrane helices and predicted to impair the correct localization of the protein into the membranes, and one residue present in the regulatory domain, which is important for protein-protein interaction.

AB - Mutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation in the basal ganglia. By using western blot analysis with specific antibody and confocal studies, we showed that wild-type C19orf12 protein was not exclusively present in mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria Associated Membrane), while mutant C19orf12 variants presented a different localization. Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein was able to relocate to the cytosol. On the contrary, mutant isoforms were not able to respond to oxidative stress. High mitochondrial calcium concentration and increased H2O2 induced apoptosis were found in fibroblasts derived from one patient as compared to controls. C19orf12 protein is a 17 kDa mitochondrial membrane-associated protein whose function is still unknown. Our in silico investigation suggests that, the glycine zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and C-terminal regions with respect to the transmembrane portion, on the contrary, are predicted to rearrange in a structural domain, which is homologs to the N-terminal regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may act as a regulatory protein for human MgtE transporters. The mutations here described affect respectively one glycine residue of the glycine zipper motifs, which are involved in dimerization of transmembrane helices and predicted to impair the correct localization of the protein into the membranes, and one residue present in the regulatory domain, which is important for protein-protein interaction.

KW - Endoplasmic reticulum-mitochondria associated membranes (ER-MAM)

KW - Mitochondria

KW - Molecular modeling

KW - Neurodegeneration with brain iron accumulation

KW - Oxidative stress

KW - Simulation

U2 - 10.3389/fgene.2015.00185

DO - 10.3389/fgene.2015.00185

M3 - Journal article

AN - SCOPUS:84939811693

SN - 1664-8021

VL - 6

JO - Frontiers in Genetics

JF - Frontiers in Genetics

M1 - 185

ER -