RESUMO
Diabetes mellitus is one of the most common genetic diseases that afflicts humans. It is not a single disease but a collection of diseases having in common an abnormal glucose-insulin relationship and a dysfunctional regulation of glucose homeostasis. Of interest is the diabetic state that results when the mitochondrial genome mutates. Epidemiological studies have shown this to occur in humans. Detailed metabolic studies that are impossible to conduct in humans have been carried out in the BHE/Cdb rat. This rat has a mutated mitochondrial ATPase 6 gene. Strategies to ameliorate the consequences of this mutation have been explored and some of the mechanisms for the transcription and translation of the mitochondrial gene product have been elucidated.
Assuntos
Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Mitocôndrias/fisiologia , Ratos Mutantes , Animais , Genes Mitocondriais/genética , Humanos , RatosRESUMO
Mitochondrial gene transcription research has exploded over the last decade. Nuclear-encoded proteins, nutrients, and hormones all work to regulate the transcription of this genome. To date, very few of the transcription factors have been shown to have negative effects on mitochondrial gene expression, although there are likely conditions where such downregulation may occur.
Assuntos
DNA Mitocondrial/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Mitocondriais/genética , Hormônios/farmacologia , Trifosfato de Adenosina/metabolismo , DNA Mitocondrial/fisiologia , Dieta , Alimentos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Genes Mitocondriais/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Transcrição Gênica/genética , Transcrição Gênica/fisiologia , Vitamina A/metabolismoRESUMO
Several nuclear hormone receptors have been localized to the mitochondrial compartment. Evidence supports the hypothesis that these receptors directly regulate mitochondrial transcription. Retinoic acid has also been shown to regulate mitochondrial transcription and function. This review discusses mechanisms of mitochondrial transcription and how retinoic acid may either indirectly or directly regulate mitochondrial transcription. How retinoic acid may affect individual nutrient requirements is also discussed.
Assuntos
DNA Mitocondrial/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores do Ácido Retinoico/metabolismo , Tretinoína/farmacologia , Animais , Sítios de Ligação , DNA Mitocondrial/genética , Previsões , Humanos , Modelos Genéticos , Regiões Promotoras Genéticas , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptores do Ácido Retinoico/genética , Receptores dos Hormônios Tireóideos/metabolismo , Transcrição Gênica , Tretinoína/metabolismoRESUMO
The BHE/Cdb rat has a maternally inherited mutation in the ATPase 6 mitochondrial gene that associates with impaired oxidative phosphorylation (OXPHOS) and glucose intolerance. A longevity study revealed that feeding an egg-rich (vitamin A-rich) diet delayed the onset of impaired glucose tolerance. Two experiments were conducted to test the hypothesis that BHE/Cdb rats require more dietary vitamin A than normal rats. Experiment 1 was a dose-response study examining OXPHOS in BHE/Cdb rats fed one of six levels of vitamin A. In experiment 2 BHE/Cdb and Sprague-Dawley rats were used. The rats were depleted of retinol stores, then repleted with 4 or 12 IU vitamin A/g diet. Vitamin A status was assessed in depleted, never depleted, and depleted/repleted rats. OXPHOS was optimized at 4 IU/g diet for the Sprague-Dawley rats and 12 IU/g diet for the BHE/Cdb rats. These results suggested that the criteria for vitamin intake adequacy in the BHE/Cdb rats is the optimization of mitochondrial OXPHOS. Using this criteria, we conclude that diabetes-prone BHE/Cdb rats require more dietary vitamin A than normal rats.
Assuntos
Mitocôndrias/metabolismo , Vitamina A/administração & dosagem , Vitamina A/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Feminino , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Masculino , Mitocôndrias Hepáticas/metabolismo , Mutação , Necessidades Nutricionais , Fosforilação Oxidativa , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Vitamina A/sangueRESUMO
The BHE/Cdb rat is a model for mitochondrial diabetes due to a mutation in the ATPase 6 gene. These rats require more dietary vitamin A to optimize mitochondrial function than do normal Sprague-Dawley rats. To determine a possible mechanism for this effect, cultured hepatocytes and hepatic tissues were studied. ATPase 6 (F0ATPase subunit a), retinoic acid receptors (RARs), and mitochondrial transcription factor A (mtTFA) gene products were determined using Western blot analysis. Northern analysis was used to determine ATPase 6, ATPase 6,8, and ND1 mRNA. Mitochondrial density was determined using confocal microscopy. Dose response studies using primary hepatocyte cultures showed that both ATPase 6 gene product and mRNA were optimized with additions of 10(-9) M retinoic acid. Retinoic acid receptors were found in the mitochondrial compartment. MtTFA levels were increased by vitamin A. Mitochondrial density was greater in the BHE/Cdb tissue than in Sprague-Dawley tissue. These results show that vitamin A affects mitochondrial function via an effect on both nuclear and mitochondrial encoded genes.
