Linking mitochondrial function to diabetes mellitus: an animal's tale

Berdanier, Carolyn D.

doi:10.1152/ajpcell.00227.2006

Cited by 13 publications

(7 citation statements)

References 67 publications

(49 reference statements)

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“…These simulations correspond to the data obtained on BHE/cdb rats, which have a mutation in ATP synthase that limits ATP production and leads to development of mild diabetes [98,99]. BHE/cdb rat islets showed reduced responsiveness to glucose stimulation and ATP content was lower than in control islets [99].…”

Section: Resultssupporting

confidence: 80%

Glucose sensing in the pancreatic beta cell: a computational systems analysis

Fridlyand

Philipson

2010

Theor Biol Med Model

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BackgroundPancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm. This leads to a closure of KATP channels, depolarization of the plasma membrane, influx of calcium and the eventual secretion of insulin. Such mechanism suggests that beta-cell metabolism should have a functional regulation specific to secretion, as opposed to coupling to contraction. The goal of this work is to uncover contributions of the cytoplasmic and mitochondrial processes in this secretory coupling mechanism using mathematical modeling in a systems biology approach.MethodsWe describe a mathematical model of beta-cell sensitivity to glucose. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, pyruvate reduction, NADH and ATP production and consumption. The mitochondrial part begins with production of NADH, which is regulated by pyruvate dehydrogenase. NADH is used in the electron transport chain to establish a proton motive force, driving the F1F0 ATPase. Redox shuttles and mitochondrial Ca2+ handling were also modeled.ResultsThe model correctly predicts changes in the ATP/ADP ratio, Ca2+ and other metabolic parameters in response to changes in substrate delivery at steady-state and during cytoplasmic Ca2+ oscillations. Our analysis of the model simulations suggests that the mitochondrial membrane potential should be relatively lower in beta cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in respiratory activity. The model demonstrates how activity of lactate dehydrogenase, uncoupling proteins and the redox shuttles can regulate beta-cell function in concert; that independent oscillations of cytoplasmic Ca2+ can lead to slow coupled metabolic oscillations; and that the relatively low production rate of reactive oxygen species in beta-cells under physiological conditions is a consequence of the relatively decreased mitochondrial membrane potential.ConclusionThis comprehensive model predicts a special role for mitochondrial control mechanisms in insulin secretion and ROS generation in the beta cell. The model can be used for testing and generating control hypotheses and will help to provide a more complete understanding of beta-cell glucose-sensing central to the physiology and pathology of pancreatic β-cells.

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Section: Resultssupporting

confidence: 80%

Glucose sensing in the pancreatic beta cell: a computational systems analysis

Fridlyand

Philipson

2010

Theor Biol Med Model

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“…Dysfunctional mitochondria have been implicated in a variety of diseases including neurodegeneration and diabetes. (1)(2)(3)(4)(5)(6) Mitochondrial DNA (mtDNA) was traditionally thought to only encode 13 protein coding genes, however, a novel class of bioactive, endogenous peptides that are encoded from small open reading frames within the mitochondrial genome has recently been discovered. (7)(8)(9)(10) These mitochondrial derived peptides (MDPs) include HN, MOTS-c and SHLPs and have distinct biological activities on metabolism and cyto-protection as well as being altered in disease states (10)(11)(12)(13)(14), providing support for a network of active mitochondrial-encoded signals that act at the cellular and organismal level.…”

Section: Introductionmentioning

confidence: 99%

Effects of air pollution on mitochondrial function, mitochondrial DNA methylation, and mitochondrial peptide expression

Breton

Song

Xiao³

et al. 2019

Mitochondrion

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Mitochondrial DNA is sensitive to damage by exogenous reactive oxygen sources, including traffic-related air pollution (TRAP). Given the important role for mitochondria in human disease, we hypothesized that prenatal air pollution exposure may be associated with mitochondrial dysfunction and that mitochondrial-derived peptides (MDPs) might protect against these effects. In in vitro studies, 24-hour exposure to nanoparticulate matter (nPM) increased oxidation of mtDNA, decreased mitochondrial consumption rate (OCR), and decreased mtDNAcn in SH-SY5Y cells. Addition of MDPs rescued these effects to varying degrees. Liver tissue taken from C57Bl/6 males exposed for 10 weeks to nPM had lower OCR, lower mtDNAcn and higher MDP levels, similar to in vitro studies. In newborn cord blood, MDP levels were positively associated with prenatal TRAP exposures. Moreover, DNA methylation of two distinct regions of the D-Loop in the mitochondria genome was associated with levels of several MDPs. Our in vitro and in vivo data indicate that TRAP can directly affect mitochondrial respiratory function and mtDNAcn. Treatment of cells with MDPs can counteract TRAP induced-effects. Lastly, we present evidence that suggests MDPs may be regulated in part by mitochondrial DNA methylation in humans.

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“…Although diabetes is a genetic-related disease, such as the mutation of mitochondrion genes (Berdanier, 2007), it can also be induced by environmental influences i.e. diet.…”

Section: Discussionmentioning

confidence: 99%

Canola Oil Influence on Azoxymethane-induced Colon Carcinogenesis, Hypertriglyceridemia and Hyperglycemia in Kunming Mice

Cichello²,

Duan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Azoxymethane (AOM) is a potent genotoxic carcinogen which specifically induces colon cancer. Hyperlipidemia and diabetes have several influences on colon cancer development, with genetic and environmental exposure aspects. Here, we investigated plasma lipid and glucose concentrations in Kunming mice randomized into four groups; control (no AOM or oil exposure), AOM control, AOM + pork oil, and AOM + canola oil. Aberrant crypt foci (ACF), plasma cholesterol, plasma triglyceride, plasma glucose and organ weight were examined 32 weeks after AOM injection. Results revealed that AOM exposure significantly increased ACF number, plasma triglyceride and glucose level. Further, male mice displayed a much higher plasma triglyceride level than female mice in the AOM control group. Dietary fat significantly inhibited AOM-induced hypertriglyceridemia, and canola oil had stronger inhibitory effect than pork oil. AOM-induced hyperglycemia had no sex-difference and was not significantly modified by dietary fat. However, AOM itself not change plasma cholesterol level. AOM significantly increased liver and spleen weight in male mice, but decreased kidney weight in female mice. On the other hand, mice testis weight decreased when fed canola oil. AOM could induce colorectal carcinogenesis, hypertriglyceridemia and hyperglycemia in Kunming mice at the same time, with subsequent studies required to investigate their genome association.

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Linking mitochondrial function to diabetes mellitus: an animal's tale

Cited by 13 publications

References 67 publications

Glucose sensing in the pancreatic beta cell: a computational systems analysis

Glucose sensing in the pancreatic beta cell: a computational systems analysis

Effects of air pollution on mitochondrial function, mitochondrial DNA methylation, and mitochondrial peptide expression

Canola Oil Influence on Azoxymethane-induced Colon Carcinogenesis, Hypertriglyceridemia and Hyperglycemia in Kunming Mice

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