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

Nicholas, Lisa M.; Valtat, B.; Medina, Anya; Andersson, Lotta E.; Abels, Mia; Mollet, Inês G.; Jain, Deepak; Eliasson, Lena; Wierup, Nils; Fex, Malin; Mulder, Hindrik

doi:10.1016/j.molmet.2017.05.005

Cited by 39 publications

(45 citation statements)

References 41 publications

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“…Interestingly, expression of PDX1, a β-cell masterregulator, was recently implicated in control of mitophagy in β-cells (Soleimanpour et al 2015). Indeed, we observed reduced expression of PDX1 in β-cells from mice lacking transcription factor B2 mitochondrial (TFB2M), where both mitophagy and autophagy were evident (Nicholas et al 2017).…”

Section: Figurementioning

confidence: 73%

“…TFAM and TFB2M are essential for transcription of the mitochondrial DNA (Ekstrand et al 2004), a prerequisite for mitochondrial biogenesis. Interestingly, a conditional knock out of Tfam or Tfb2m in β-cells results in impaired fuel-stimulated insulin secretion and diabetes in mice (Silva et al 2000, Nicholas et al 2017.…”

Section: Figurementioning

confidence: 99%

“…Whilst the role of TFAM in pancreatic β-cells has been well characterised (Silva et al 2000), it is only recently that we have elucidated the importance of TFB2M in mitochondrial and cellular function of pancreatic β-cells, using a mouse model of a β-cell specific homozygous and heterozygous knockout of Tfb2m, as well as in rat clonal insulin-producing cells (Nicholas et al 2017). A striking result of this study was how rapidly these perturbations evolve in Tfb2m-deficient mice compared to those previously seen in mice with a β-cell-specific loss of either Tfam (Silva et al 2000) or Tfb1m .…”

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

“…Ultimately, however, widespread mitochondrial dysfunction overwhelms cell-protective systems, such as mitochondrial unfolded protein response, leading to β-cell dysfunction as well as increased apoptosis and loss of β-cell mass. The rapid onset and dramatic consequences of TFB2M deficiency suggest an unforeseen critical role for this mitochondrial transcription factor (Nicholas et al 2017). Loss of Tfb2m in β-cells from 18-day-old β-Tfb2m −/− mice and in INS1 832/13 cells also activates both autophagy and mitophagy (Nicholas et al 2017).…”

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

“…The rapid onset and dramatic consequences of TFB2M deficiency suggest an unforeseen critical role for this mitochondrial transcription factor (Nicholas et al 2017). Loss of Tfb2m in β-cells from 18-day-old β-Tfb2m −/− mice and in INS1 832/13 cells also activates both autophagy and mitophagy (Nicholas et al 2017). An increased number of mitochondria targeted to LC3-positive vesicles are observed, which implies either impaired autophagosome-lysosome fusion or increased autophagy flux through mitophagy.…”

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

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The pathogenetic role of β-cell mitochondria in type 2 diabetes

Fex

Nicholas

Vishnu

et al. 2018

Journal of Endocrinology

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Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.

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Section: Figurementioning

confidence: 73%

Section: Figurementioning

confidence: 99%

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

Section: Transcriptional and Translational Control Of Mitochondrial Fmentioning

confidence: 99%

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The pathogenetic role of β-cell mitochondria in type 2 diabetes

Fex

Nicholas

Vishnu

et al. 2018

Journal of Endocrinology

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Roles of Mitochondrial DNA in Energy Metabolism

Bhatia

Wang

2017

Advances in Experimental Medicine and Biology

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Mitochondria are independent double-membrane organelles responsible for energy production, specifically by completing oxidative phosphorylation. Mitochondria are essential to regulate energy metabolism, signaling pathways, and cell death. Mitochondrial DNA (mtDNA) can be altered by metabolic disorders, oxidative stress, or inflammation in the progression and development of various diseases. In this chapter, we overview the role of mtDNA in energy metabolism and the diseases that are associated with mtDNA abnormality, with a special focus on the major factors which regulate the mechanism of mtDNA in metabolism.

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Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice

et al. 2019

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Aims/hypothesis Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal highfat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. Methods Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. Results Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose-(p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca 2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05).

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

Cited by 39 publications

References 41 publications

The pathogenetic role of β-cell mitochondria in type 2 diabetes

The pathogenetic role of β-cell mitochondria in type 2 diabetes

Roles of Mitochondrial DNA in Energy Metabolism

Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice

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