Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes

Abstract

We have previously identified transcription factor B1 mitochondrial (TFB1M) as a type 2 diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D, we created a β-cell-specific knockout of Tfb1m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1m(-/-) mice exhibited retarded glucose clearance owing to impaired insulin secretion. β-Tfb1m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine dimethylation of 12S ribosomal RNA (rRNA). Here, we found that the levels of TFB1M and mitochondrial-encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1m(-/-) islets. Furthermore, the levels of reactive oxygen species (ROS) in response to cellular stress were increased whereas induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+) cells in the islets. Taken together, our findings demonstrate that Tfb1m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes owing to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.

Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells

“…A striking result of this study was how rapidly these perturbations evolved in Tfb2m -deficient mice compared to those previously seen in mice with a β-cell specific loss of either Tfam [10] or Tfb1m [12]. At seven weeks of age, Tfam -deficient mice display perturbed mtDNA expression and consequently severe respiratory chain deficiency in pancreatic β-cells.…”

Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure

“…Loss of mitochondrial transcription factor A (TFAM), an obligatory mitochondrial DNA (mtDNA) transcription factor in beta cells, results in spontaneous hyperglycaemia associated with reduced insulin secretion and beta cell loss [15]. Loss of the mitochondrial translation factor transcription factor B1 mitochondrial (TFB1M) specifically from beta cells leads to beta cell dysfunction and loss of beta cell mass [16]. Taken together, these findings support the hypothesis that impaired OxPhos function contributes to the pathogenesis of diabetes.…”

“…Accordingly, mice heterozygous for Tfb1m deficiency exhibit reduced levels of TFB1M in islets, impaired mitochondrial function and reduced insulin release in response to glucose in vivo and in vitro. Additionally, in mice in which Tfbim is specifically knocked out in beta cells, ATP is depleted and the level of reactive oxygen species (ROS) is increased, which led to loss of beta cell function and mass owing to increased apoptosis and necrosis [16].…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…An in vitro model in which Tfb1m expression was reduced INS-1 832/13 cells by siRNA closely reproduced the in vivo data. In a subsequent study (480), mice possessing a ␤-cell-specific knockout of Tfb1m developed diabetes, while the isolated islets showed profound bioenergetic deficiencies and disturbed mitochondrial morphology.…”