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 Sabine Hutchinson, B Cannon, Claes Wahlestedt, Bente Pedersen, James A Timmons

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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.--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. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?
Original languageEnglish
Pages (from-to)3653 - 3665
Number of pages13
JournalFASEB Journal
Volume21
Issue number13
Publication statusPublished - 2007

Cite this

Scheele, C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., ... Timmons, J. A. (2007). Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration? FASEB Journal, 21(13), 3653 - 3665.
Scheele, Camilla ; Nielsen, Anders Rinnov ; Walden, Tomas B ; Sewell, Dean A ; Fischer, Christian P ; Brogan, Robert J ; Petrovic, Natasa ; Larsson, Ola ; Tesch, Per A ; Wennmalm, Kristian ; Hutchinson, Dana Sabine ; Cannon, B ; Wahlestedt, Claes ; Pedersen, Bente ; Timmons, James A. / Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?. In: FASEB Journal. 2007 ; Vol. 21, No. 13. pp. 3653 - 3665.
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title = "Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?",
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.--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. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?",
author = "Camilla Scheele and Nielsen, {Anders Rinnov} and Walden, {Tomas B} and Sewell, {Dean A} and Fischer, {Christian P} and Brogan, {Robert J} and Natasa Petrovic and Ola Larsson and Tesch, {Per A} and Kristian Wennmalm and Hutchinson, {Dana Sabine} and B Cannon and Claes Wahlestedt and Bente Pedersen and Timmons, {James A}",
year = "2007",
language = "English",
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Scheele, C, Nielsen, AR, Walden, TB, Sewell, DA, Fischer, CP, Brogan, RJ, Petrovic, N, Larsson, O, Tesch, PA, Wennmalm, K, Hutchinson, DS, Cannon, B, Wahlestedt, C, Pedersen, B & Timmons, JA 2007, 'Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?', FASEB Journal, vol. 21, no. 13, pp. 3653 - 3665.

Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration? / Scheele, Camilla; Nielsen, Anders Rinnov; Walden, Tomas B; Sewell, Dean A; Fischer, Christian P; Brogan, Robert J; Petrovic, Natasa; Larsson, Ola; Tesch, Per A; Wennmalm, Kristian; Hutchinson, Dana Sabine; Cannon, B; Wahlestedt, Claes; Pedersen, Bente; Timmons, James A.

In: FASEB Journal, Vol. 21, No. 13, 2007, p. 3653 - 3665.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?

AU - Scheele, Camilla

AU - Nielsen, Anders Rinnov

AU - Walden, Tomas B

AU - Sewell, Dean A

AU - Fischer, Christian P

AU - Brogan, Robert J

AU - Petrovic, Natasa

AU - Larsson, Ola

AU - Tesch, Per A

AU - Wennmalm, Kristian

AU - Hutchinson, Dana Sabine

AU - Cannon, B

AU - Wahlestedt, Claes

AU - Pedersen, Bente

AU - Timmons, James A

PY - 2007

Y1 - 2007

N2 - 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.--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. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?

AB - 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.--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. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?

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Scheele C, Nielsen AR, Walden TB, Sewell DA, Fischer CP, Brogan RJ et al. Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration? FASEB Journal. 2007;21(13):3653 - 3665.