A novel mutation in the NADH dehydrogenase (ubiquinone) 1 alpha sub-complex 4 (Ndufa4) gene links mitochondrial dysfunction to the development of diabetes in a rodent model

Abstract

The mechanisms underlying diabetes remain unresolved. The Cohen Diabetic rat represents a model of diet-induced diabetes in which the disease is induced after exposure to a diabetogenic diet (DD) in the diabetes sensitive (CDs/y) but not in the resistant (CDr/y) strain. Diet imposes a metabolic strain that leads to diabetes in the appropriate genetic background. We previously identified through whole genome linkage analysis a diabetes-related QTL on RNO4 which incorporates NADH dehydrogenase (ubiquinone) 1 alpha sub-complex 4 (Ndufa4), a nuclear gene that affects mitochondrial function. We currently sequenced the gene and found a major deletion in CDs/y that leads to lack of expression of the NDUFA4 protein that is reported to be involved in the activities of mitochondrial complexes I and IV. In the absence of NDUFA4 in the diabetic CDs/y on DD, complex I activity is reduced in comparison to the non-diabetic CDs/y on regular diet and CDr/y on either diet; complex IV activity is reduced in both strains provided DD, and thus as result of diet and unrelated to the gene mutation. Tissue ATP fails to increase in diabetic CDs/y in response to DD, in comparison to non-diabetic CDr/y on DD. Plasma MDA levels are elevated in CDs/y on DD, while SOD1 and SOD2 levels fail to increase, indicating increased oxidative stress and inability of the pancreas to generate an appropriate anti-oxidative stress response. These findings suggest that the Ndufa4 mutation in CDs/y on DD is directly associated with mitochondrial dysfunction which we attribute to the lack of expression of NDUFA4 and to diet, and which prevents the anticipated increase in ATP production. The resulting enhanced oxidative stress impairs the ability of the pancreas to secrete insulin, leading to the development of diabetes. This is the first demonstration of an inherited mutation in a nuclear gene that adversely affects mitochondrial function and promotes diet-induced diabetes.