Mitochondrial metabolism plays a critical role in the processes that control both secretion and action of insulin. In the pancreatic β-cell, fuels stimulating insulin secretion elicit signals from metabolism in mitochondria. These account for both the triggering (ATP:ADP ratio) and amplifying pathways that control exocytosis of insulin. In insulin target tissues, mitochondrial metabolism controls insulin sensitivity. For instance, impairments of oxidative phosphorylation and fatty acid metabolism in mitochondria have been linked to insulin resistance.
Transcriptional control of the mitochondrial genome plays a crucial role in mitochondrial metabolism, ensuring that metabolically active cells harbour a sufficient number of mitochondria equipped with the appropriate enzymes and proteins. While the majority of mitochondrial proteins are encoded by the nuclear genome, 13 essential proteins are encoded by mitochondrial DNA; these include critical components of the respiratory chain. Mitochondrial transcription is controlled by a complex of three nuclear-encoded proteins: Transcription Factor A Mitochondrial (TFAM), Transcription Factor B1 Mitochondrial (TFB1M), and Transcription Factor B2 Mitochondrial (TFB2M). Of these, TFAM is the most important, but TFB2M, and perhaps TFB1M, also enhance transcription. The role of TFB1M is more likely to serve as an RNA methyl-transferase, controlling translation of mitochondrial proteins.
In addition to the specific mitochondrial transcription factors, a number of nuclear-encoded proteins are important regulators of mitochondrial function. These include nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor co-factor 1α (PGC-1α). Charlotte Ling, Leif Groop and co-workers have previously shown that PGC-1α plays an important role to regulate mitochondrial metabolism. Its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Moreover, in human islets, PGC-1α mRNA expression was strongly reduced, and correlated with impaired insulin secretion in patients with Type 2 Diabetes. Interestingly, a common PGC-1α Gly482Ser polymorphism was associated with reduced PGC-1α mRNA expression and reduced insulin secretion. The possible epigenetic influence was further supported by that the PGC-1α gene promoter in diabetic islets showed a 2-fold increase in DNA methylation. The epigenetic mechanisms that control expression of genes involved oxidative phosphorylation is now studied intensely. Ling and co-workers recently found that genetic variation and age are associated with expression of ATP5O mRNA in skeletal muscle and glucose disposal rate. This suggests that ATP5O, in cooperation with other OXPHOS genes, plays a role in the regulation of in vivo glucose metabolism.
Methodological and technical platform
The LUDC Mitochondria action group has established/employs an array of useful and cutting edge methodology. This includes genome-wide association studies (GWAS), metabolomics, Seahorse XF24 Flux analyzer, transgenic technology, RNA interference (RNAi). The interaction between genetics, functional genomics, and β-cell physiology generates impact, synergies, and consequently added value for the LUDC.
The LUDC Mitochondria action group is focusing on a number of long-term goals.
• Understand the role of mitochondria in β-cell stimulus-secretion coupling
• Reveal epigenetic control of genes relevant to mitochondrial function
• Elucidate transcriptional and translational control of mitochondrial gene products
• Identify genes associated with Type 2 Diabetes and its accompanying traits
• Reveal mitochondrial dysfunction in Type 2 Diabetes
• Understand mitochondrial alterations in animal models for Type 2 Diabetes
Mulder H, Ling C.Mitochondrial dysfunction in pancreatic beta-cells in Type 2 diabetes. Mol Cell Endocrinol. 2009 Jan 15;297(1-2):34-40.
Rönn T, Poulsen P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C. Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins. PLoS ONE. 2009;4(3):e4793.
Rönn T, Poulsen P, Hansson O, Holmkvist J, Almgren P, Nilsson P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C.Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia. 2008 Jul;51(7):1159-68.
Ling C, Del Guerra S, Lupi R, Rönn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia. 2008 Apr;51(4):615-22.
Ling C, Wegner L, Andersen G, Almgren P, Hansen T, Pedersen O, Groop L, Vaag A, Poulsen P. Impact of the peroxisome proliferator activated receptor-gamma coactivator-1beta (PGC-1beta) Ala203Pro polymorphism on in vivo metabolism, PGC-1beta expression and fibre type composition in human skeletal muscle. Diabetologia. 2007 Aug;50(8):1615-20.
Ling C, Poulsen P, Carlsson E, Ridderstråle M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A. Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest. 2004 Nov;114(10):1518-26.
Last updated: October 27, 2010
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