Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure.
A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function, which can have deleterious effects. Critical questions are whether mitochondrial dysfunction progressively declines after birth, and if so, what mechanism might underlie this process. To address this, we developed a model of intrauterine growth retardation (IUGR) in the rat that leads to diabetes in adulthood. Reactive oxygen species (ROS) production and oxidative stress gradually increased in IUGR islets. ATP production was impaired and continued to deteriorate with age. The activities of complex I and III of the electron transport chain progressively declined in IUGR islets. Mitochondrial DNA point mutations accumulated with age and were associated with decreased mitochondrial DNA content and reduced expression of mitochondria-encoded genes in IUGR islets. Mitochondrial dysfunction resulted in impaired insulin secretion. These results demonstrate that IUGR induces mitochondrial dysfunction in the fetal beta-cell, leading to increased production of ROS, which in turn damage mitochondrial DNA. A self-reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues.
Simmons
Rebecca A
RA
Department of Pediatrics Children's Hospital Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. rsimmons@mail.med.upenn.edu
Suponitsky-Kroyter
Irena
I
Selak
Mary A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D004272:DNA, Mitochondrial / Q000235:genetics*; D005317:Fetal Growth Retardation; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D001786:Blood Glucose; D004272:DNA, Mitochondrial; D007328:Insulin; D012333:RNA, Messenger; D000255:Adenosine Triphosphate