PT - JOURNAL ARTICLE AU - Gaurav Verma AU - Alexander Bowen AU - Alexander Hamilton AU - Jonathan Esguerra AU - Alexandros Karagiannopoulos AU - Luis Rodrigo Cataldo AU - Claire Lyons AU - Elaine Cowan AU - Malin Fex AU - Hindrik Mulder TI - DIMT1, a regulator of ribosomal biogenesis, controls β-cell protein synthesis, mitochondrial function and insulin secretion AID - 10.1101/2020.09.27.313262 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.09.27.313262 4099 - http://biorxiv.org/content/early/2020/09/27/2020.09.27.313262.short 4100 - http://biorxiv.org/content/early/2020/09/27/2020.09.27.313262.full AB - We previously reported that transcription factor B1 mitochondrial (TFB1M) is involved in the pathogenesis of type 2 diabetes (T2D) owing to mitochondrial dysfunction. Here, we describe that dimethyladenosine transferase 1 homolog (DIMT1), a homologue of TFB1M, is expressed and active in pancreatic β-cells. Like TFB1M, it has been implicated in control of ribosomal RNA (rRNA) but its role in β-cells or T2D remains to be identified. Silencing of DIMT1 impacted mitochondrial function, leading to reduced expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate (OCR), dissipated mitochondrial membrane potential (ΔΨm) and caused a lower rate of ATP production (mATP). In addition, DIMT1 knockdown slowed the rate of protein synthesis. In accordance with these findings, DIMT1-deficiency perturbed insulin secretion in rodent and human β-cell lines. These effects are likely a result of destabilization of ribosomal assembly, involving NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1). These are two critical ribosomal subunits proteins, whose interactions were perturbed upon DIMT1-deficiency, thereby disturbing protein synthesis in β-cells. Thus, we have here highlighted a role of DIMT1 in ribosomal biogenesis that perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both being potential pathogenetic factors in T2D.Competing Interest StatementThe authors have declared no competing interest.