Ribosomal biogenesis regulator DIMT1 controls β-cell protein synthesis, mitochondrial function, and insulin secretion
(2022) In The Journal of biological chemistry 298(3).- Abstract
We previously reported that loss of mitochondrial transcription factor B1 (TFB1M) leads to mitochondrial dysfunction and is involved in the pathogenesis of type 2 diabetes (T2D). Whether defects in ribosomal processing impact mitochondrial function and could play a pathogenetic role in β-cells and T2D is not known. To this end, we explored expression and the functional role of dimethyladenosine transferase 1 homolog (DIMT1), a homolog of TFB1M and a ribosomal RNA (rRNA) methyltransferase implicated in the control of rRNA. Expression of DIMT1 was increased in human islets from T2D donors and correlated positively with expression of insulin mRNA, but negatively with insulin secretion. We show that silencing of DIMT1 in insulin-secreting... (More)
We previously reported that loss of mitochondrial transcription factor B1 (TFB1M) leads to mitochondrial dysfunction and is involved in the pathogenesis of type 2 diabetes (T2D). Whether defects in ribosomal processing impact mitochondrial function and could play a pathogenetic role in β-cells and T2D is not known. To this end, we explored expression and the functional role of dimethyladenosine transferase 1 homolog (DIMT1), a homolog of TFB1M and a ribosomal RNA (rRNA) methyltransferase implicated in the control of rRNA. Expression of DIMT1 was increased in human islets from T2D donors and correlated positively with expression of insulin mRNA, but negatively with insulin secretion. We show that silencing of DIMT1 in insulin-secreting cells impacted mitochondrial function, leading to lower expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate, dissipated mitochondrial membrane potential, and a slower rate of ATP production. In addition, the rate of protein synthesis was retarded upon DIMT1-deficiency. Consequently, we found that DIMT1 deficiency led to perturbed insulin secretion in rodent cell lines and islets, as well as in a human β-cell line. We observed defects in rRNA processing and reduced interactions between NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1), critical ribosomal subunit RNA proteins, the dysfunction of which may play a part in disturbing protein synthesis in β-cells. In conclusion, DIMT1 deficiency perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both potential pathogenetic processes in T2D.
(Less)
- author
- organization
-
- Mitochondrial Medicine (research group)
- Diabetes - Molecular Metabolism (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- Division of Molecular Hematology (DMH)
- RNA and Stem Cell Biology (research group)
- Stem Cell Center
- Translational Muscle Research (research group)
- Diabetes - Islet Cell Exocytosis (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- publishing date
- 2022-02-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- The Journal of biological chemistry
- volume
- 298
- issue
- 3
- article number
- 101692
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:35148993
- scopus:85126393712
- ISSN
- 1083-351X
- DOI
- 10.1016/j.jbc.2022.101692
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
- id
- 84ae6e52-9de9-415a-b6dd-d6298979f377
- date added to LUP
- 2022-02-14 05:16:16
- date last changed
- 2024-09-13 12:30:25
@article{84ae6e52-9de9-415a-b6dd-d6298979f377, abstract = {{<p>We previously reported that loss of mitochondrial transcription factor B1 (TFB1M) leads to mitochondrial dysfunction and is involved in the pathogenesis of type 2 diabetes (T2D). Whether defects in ribosomal processing impact mitochondrial function and could play a pathogenetic role in β-cells and T2D is not known. To this end, we explored expression and the functional role of dimethyladenosine transferase 1 homolog (DIMT1), a homolog of TFB1M and a ribosomal RNA (rRNA) methyltransferase implicated in the control of rRNA. Expression of DIMT1 was increased in human islets from T2D donors and correlated positively with expression of insulin mRNA, but negatively with insulin secretion. We show that silencing of DIMT1 in insulin-secreting cells impacted mitochondrial function, leading to lower expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate, dissipated mitochondrial membrane potential, and a slower rate of ATP production. In addition, the rate of protein synthesis was retarded upon DIMT1-deficiency. Consequently, we found that DIMT1 deficiency led to perturbed insulin secretion in rodent cell lines and islets, as well as in a human β-cell line. We observed defects in rRNA processing and reduced interactions between NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1), critical ribosomal subunit RNA proteins, the dysfunction of which may play a part in disturbing protein synthesis in β-cells. In conclusion, DIMT1 deficiency perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both potential pathogenetic processes in T2D.</p>}}, author = {{Verma, Gaurav and Bowen, Alexander and Gheibi, Sevda and Hamilton, Alexander and Muthukumar, Sowndarya and Cataldo, Luis Rodrigo and Asplund, Olof and Esguerra, Jonathan and Karagiannopoulos, Alexandros and Lyons, Claire and Cowan, Elaine and Bellodi, Cristian and Prasad, Rashmi and Fex, Malin and Mulder, Hindrik}}, issn = {{1083-351X}}, language = {{eng}}, month = {{02}}, number = {{3}}, publisher = {{American Society for Biochemistry and Molecular Biology}}, series = {{The Journal of biological chemistry}}, title = {{Ribosomal biogenesis regulator DIMT1 controls β-cell protein synthesis, mitochondrial function, and insulin secretion}}, url = {{http://dx.doi.org/10.1016/j.jbc.2022.101692}}, doi = {{10.1016/j.jbc.2022.101692}}, volume = {{298}}, year = {{2022}}, }