Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of brown adipocyte differentiation and thermogenesis. The PPARγ gene produces two isoforms, PPARγ1 and PPARγ2. PPARγ2 is identical to PPARγ1 except for additional 30 amino acids present in the N-terminus of PPARγ2. Here we report that the C-terminally truncated form of PPARγ2 is predominantly present in the mitochondrial matrix of brown adipocytes and that it binds to the D-loop region of mitochondrial DNA (mtDNA), which contains the promoter for mitochondrial electron transport chain (ETC) genes. Expression of mitochondrially targeted MLS-PPARγ2 in brown adipocytes increases mtDNA-encoded ETC gene expression concomitant with enhanced mitochondrial respiration. These results suggest that direct regulation of mitochondrially encoded ETC gene expression by mitochondrial PPARγ2, in part, underlies the isoform-specific role for PPARγ2 in brown adipocytes.
Highlights
A growing body of evidence from recent studies reveals that nuclear transcription factors translocate to mitochondria and play a role in a cell- or tissue-specific manner
A truncated PPAR gamma 2 in brown adipocyte mitochondria fractionation of brown adipose tissue (BAT) and western blot analysis with anti-PPARγ2 antibody unexpectedly revealed that while a ~57 kDa protein representing PPARγ2 was enriched in the nuclear fraction, a ~52 kDa protein was predominantly present in the cytoplasmic and mitochondrial fractions (Fig 1B)
The present study identifies the truncated form of PPARγ2 (52 kDa) that is highly enriched in brown adipocyte mitochondria and regulates mitochondrial DNA (mtDNA)-encoded electron transport chain (ETC) gene expression
Summary
A growing body of evidence from recent studies reveals that nuclear transcription factors translocate to mitochondria and play a role in a cell- or tissue-specific manner. Thyroid receptor (TRα isoform p43), MEF2D, STAT3, and CREB translocate to mitochondria and directly modulate mitochondrial DNA transcription in response to specific stimuli [1,2,3,4,5], indicating that nuclear transcription factors can control mitochondrial function via transcriptional regulation of mitochondrial genome. A growing number of nuclear receptors such as glucocorticoid receptor (GR), vitamin D receptor (VDR), retinoid X receptor (RXR) and retinoic acid receptor (RAR) have been found in the mitochondria of various cells and tissues, their function in mitochondria has not been explored [10]
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