Altered regulation of the PINK1 locus: A link between type 2 diabetes and neurodegeneration?

Camilla Scheele, Anders Rinnov Nielsen, Tomas B. Walden, Dean A. Sewell, Christian P. Fischer, Robert J. Brogan, Natasa Petrovic, Ola Larsson, Per A. Tesch, Kristian Wennmalm, Dana S. Hutchinson, Barbara Cannon, Claes Wahlestedt, Bente K. Pedersen, James A. Timmons

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson's. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis.

Original languageEnglish (US)
Pages (from-to)3653-3665
Number of pages13
JournalFASEB Journal
Volume21
Issue number13
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

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Keywords

  • Altered gene regulation
  • Inactivity
  • Metabolism
  • Mitochondria

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Scheele, C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., Petrovic, N., Larsson, O., Tesch, P. A., Wennmalm, K., Hutchinson, D. S., Cannon, B., Wahlestedt, C., Pedersen, B. K., & Timmons, J. A. (2007). Altered regulation of the PINK1 locus: A link between type 2 diabetes and neurodegeneration? FASEB Journal, 21(13), 3653-3665. https://doi.org/10.1096/fj.07-8520com