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Cited by 194Pancreatic function and diabetesMitochondrial Function and PathologyBirth, Development, and Health

Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure.

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Simmons, Rebecca A., Suponitsky-Kroyter, Irena, Selak, Mary A.·2005·Journal of Biological Chemistry
DOI 10.1074/jbc.m505695200
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Abstract

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 β-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 β-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues. 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 β-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 β-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues. Epidemiological studies have revealed strong statistical links between poor fetal growth and the subsequent development of type 2 diabetes in adulthood (1.Barker D.J.P. Osmond C. Lancet. 1986; I: 1077-1081Abstract Scopus (1904) Google Scholar, 2.Barker D. Hales J.C.N. Fall C.H. Osmond C. Phipps K. Clark P.M. Diabetologia. 1993; 36: 62-67Crossref PubMed Scopus (2153) Google Scholar, 3.Ravelli G. Stein Z.A. Susser M.W. N. Engl. J. Med. 1995; 295: 349-354Crossref Scopus (1204) Google Scholar, 4.Valdez R. Athens M.A. Thompson G.H. Bradshaw B.S. Stern M.P. Diabetologia. 1994; 37: 624-631Crossref PubMed Scopus (464) Google Scholar, 5.Hales C.N. Barker D.J.P. Clark P.M.S. Cox L.J. Fall C. Osmond C. Br. Med. J. 1991; 303: 1019-1022Crossref PubMed Scopus (2211) Google Scholar, 6.Rich-Edwards J.W. Colditz G.A. Stampfer M.J. Willett W.C. Gillman M.W. Hennekens C.H. Speizer F.E. Manson J.E. Ann. Intern. Med. 1999; 130: 278-284Crossref PubMed Google Scholar). These associations have led to the “fetal origins of adult disease hypothesis,” which states that “to ensure fetal survival, adaptations to intrauterine deprivation result in a permanent reprogramming of key organ systems” (2.Barker D. Hales J.C.N. Fall C.H. Osmond C. Phipps K. Clark P.M. Diabetologia. 1993; 36: 62-67Crossref PubMed Scopus (2153) Google Scholar). Both insulin action and insulin secretion are impaired in individuals who were growth-retarded at birth (7.Lithell H.O. McKeigue P.M. Berglund L. Mohsen R. Lithell U.B. Leon D.A. Br. Med. J. 1996; 312: 406-410Crossref PubMed Scopus (639) Google Scholar, 8.Jaquet D. Gaboriau P. Czernichow P. Levy-Marchal C. J. Clin. Endocrinol. Metab. 2000; 85: 1401-1406Crossref PubMed Scopus (338) Google Scholar, 9.Jensen C.B. Storgaard H. Dela F. Holst J.J. Madsbad S. Vaag A.A. Diabetes. 2002; 51: 1271-1280Crossref PubMed Scopus (163) Google Scholar, 10.Leger J. Levy-Marchal C. Bloch J. Pinet A. Chevenne D. Porquet D. Collin D. Czernichow P. Br. Med. J. 1997; 315: 341-347Crossref PubMed Scopus (350) Google Scholar, 11.Crowther N.J. Trusler J. Cameron N. Toman M. Gray I.P. Diabetologia. 2000; 43: 978-985Crossref PubMed Scopus (52) Google Scholar, 12.Cook J.T. Levy J.C. Page R.C. Shaw J.A. Hattersley A.T. Turner R.C. Br. Med. J. 1993

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  • Low levels of ROS are necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on β-cell function.

    “Low levels of ROS are necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on ␤-cell function (254 -256).”

    From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [256]

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Authors
Simmons, R. A., Suponitsky-Kroyter, I., & Selak, M. A.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Simmons, Rebecca A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-08
Volume
280
Issue
31
Pages
28785-28791
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m505695200
OpenAlex
W2099231263
Cited by
194
References
82
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 13 · 2013: 13 · 2012: 16
FWCI
12.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG20898, R01AG020898)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, R01DK055704, DK-55704, P30DK019525)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
Keywords
fetal growth restriction, mitochondrial dysfunction, mitochondrial DNA mutations, beta-cell failure, type 2 diabetes, reactive oxygen species, oxidative stress, electron transport chain, insulin secretion, mitochondrial DNA content, ATP production, rat model, aging, developmental origins of health and disease, pancreatic islets, mitochondrial complex I, mitochondrial complex III
MeSH terms
Insulin Secretion, Adenosine Triphosphate, Animals, Blood Glucose, Body Weight, DNA, Mitochondrial, Fetal Growth Retardation, Insulin, Islets of Langerhans, Male, Mitochondria, Mutation, Reference Values, RNA, Messenger, Rats, Sprague-Dawley, Gene Expression Regulation, Developmental, Rats

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