Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?
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
Camilla
C
Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden. camilla.scheele@gmail.com
Nielsen
Anders Rinnov
AR
Walden
Tomas B
TB
Sewell
Dean A
DA
Fischer
Christian P
CP
Brogan
Robert J
RJ
Petrovic
Natasa
N
Larsson
Ola
O
Tesch
Per A
PA
Wennmalm
Kristian
K
Hutchinson
Dana S
DS
Cannon
Barbara
B
Wahlestedt
Claes
C
Pedersen
Bente K
BK
Timmons
James A
JA
D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000150:complications / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase