Limits...
Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta.

Liesa M, Borda-d'Agua B, Medina-Gómez G, Lelliott CJ, Paz JC, Rojo M, Palacín M, Vidal-Puig A, Zorzano A - PLoS ONE (2008)

Bottom Line: Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein.This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells.Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha).

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT

Background: There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression.

Methodology/principal findings: Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1beta increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha).

Conclusions/significance: Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.

Show MeSH

Related in: MedlinePlus

Hepatic Mfn2 levels are diminished in PGC-1β KO mice.Livers from 4- or 8- month-old wild-type (WT, black bars) and PGC-1β KO male mice (KO, white bars) were used to obtain total RNA and protein. (A) Representative image from a Western blot with specific detection of Mfn2 and Porin in liver lysates from WT or KO mice. Graph represents mean±SEM of Mfn2 levels related to Porin (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics in total lysates (Mfn1, OPA1, Drp1 and Fis1). Graph represents mean±SEM of protein levels relative to Porin values (n = 6 mice per group). (C) Real-time PCR analysis of Mfn2 from WT and KO mice. Graph represents mean±SEM and data are expressed as values of Mfn2 relative to 36B4 mRNA levels (n = 8 mice per group). *, statistical difference at p<0.01. (D) Abundance of the ETC subunits in mitochondrial fractions (n = 6 mice per group). Single subunits of complexes I to V of the ETC were detected with specific antibodies. Graph represents mean±SEM and data are expressed as values relative to Porin expression. *, statistical difference at p<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2570954&req=5

pone-0003613-g006: Hepatic Mfn2 levels are diminished in PGC-1β KO mice.Livers from 4- or 8- month-old wild-type (WT, black bars) and PGC-1β KO male mice (KO, white bars) were used to obtain total RNA and protein. (A) Representative image from a Western blot with specific detection of Mfn2 and Porin in liver lysates from WT or KO mice. Graph represents mean±SEM of Mfn2 levels related to Porin (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics in total lysates (Mfn1, OPA1, Drp1 and Fis1). Graph represents mean±SEM of protein levels relative to Porin values (n = 6 mice per group). (C) Real-time PCR analysis of Mfn2 from WT and KO mice. Graph represents mean±SEM and data are expressed as values of Mfn2 relative to 36B4 mRNA levels (n = 8 mice per group). *, statistical difference at p<0.01. (D) Abundance of the ETC subunits in mitochondrial fractions (n = 6 mice per group). Single subunits of complexes I to V of the ETC were detected with specific antibodies. Graph represents mean±SEM and data are expressed as values relative to Porin expression. *, statistical difference at p<0.05.

Mentions: Liver is a crucial metabolic organ and shows high mitochondrial activity. PGC-1β KO mice also show reduced hepatic ETC gene expression [20]. On the basis of these observations, we next examined whether hepatic Mfn2 expression was altered in PGC-1β KO mice. Hepatic lysates from PGC-1β KO mice were obtained and analyzed by Western blot. Mfn2 protein levels were reduced by 65% in KO livers compared to the control group (Fig. 6A). This decrease was specific since among other proteins involved in mitochondrial dynamics only a modest 12% increase in Fis1 levels was detected (Fig. 6B). Similar results were obtained in mitochondrial fractions (data not shown). Mfn2 mRNA levels were also reduced by 25% in livers from PGC-1β KO mice (Fig. 6C).


Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta.

Liesa M, Borda-d'Agua B, Medina-Gómez G, Lelliott CJ, Paz JC, Rojo M, Palacín M, Vidal-Puig A, Zorzano A - PLoS ONE (2008)

Hepatic Mfn2 levels are diminished in PGC-1β KO mice.Livers from 4- or 8- month-old wild-type (WT, black bars) and PGC-1β KO male mice (KO, white bars) were used to obtain total RNA and protein. (A) Representative image from a Western blot with specific detection of Mfn2 and Porin in liver lysates from WT or KO mice. Graph represents mean±SEM of Mfn2 levels related to Porin (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics in total lysates (Mfn1, OPA1, Drp1 and Fis1). Graph represents mean±SEM of protein levels relative to Porin values (n = 6 mice per group). (C) Real-time PCR analysis of Mfn2 from WT and KO mice. Graph represents mean±SEM and data are expressed as values of Mfn2 relative to 36B4 mRNA levels (n = 8 mice per group). *, statistical difference at p<0.01. (D) Abundance of the ETC subunits in mitochondrial fractions (n = 6 mice per group). Single subunits of complexes I to V of the ETC were detected with specific antibodies. Graph represents mean±SEM and data are expressed as values relative to Porin expression. *, statistical difference at p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2570954&req=5

pone-0003613-g006: Hepatic Mfn2 levels are diminished in PGC-1β KO mice.Livers from 4- or 8- month-old wild-type (WT, black bars) and PGC-1β KO male mice (KO, white bars) were used to obtain total RNA and protein. (A) Representative image from a Western blot with specific detection of Mfn2 and Porin in liver lysates from WT or KO mice. Graph represents mean±SEM of Mfn2 levels related to Porin (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics in total lysates (Mfn1, OPA1, Drp1 and Fis1). Graph represents mean±SEM of protein levels relative to Porin values (n = 6 mice per group). (C) Real-time PCR analysis of Mfn2 from WT and KO mice. Graph represents mean±SEM and data are expressed as values of Mfn2 relative to 36B4 mRNA levels (n = 8 mice per group). *, statistical difference at p<0.01. (D) Abundance of the ETC subunits in mitochondrial fractions (n = 6 mice per group). Single subunits of complexes I to V of the ETC were detected with specific antibodies. Graph represents mean±SEM and data are expressed as values relative to Porin expression. *, statistical difference at p<0.05.
Mentions: Liver is a crucial metabolic organ and shows high mitochondrial activity. PGC-1β KO mice also show reduced hepatic ETC gene expression [20]. On the basis of these observations, we next examined whether hepatic Mfn2 expression was altered in PGC-1β KO mice. Hepatic lysates from PGC-1β KO mice were obtained and analyzed by Western blot. Mfn2 protein levels were reduced by 65% in KO livers compared to the control group (Fig. 6A). This decrease was specific since among other proteins involved in mitochondrial dynamics only a modest 12% increase in Fis1 levels was detected (Fig. 6B). Similar results were obtained in mitochondrial fractions (data not shown). Mfn2 mRNA levels were also reduced by 25% in livers from PGC-1β KO mice (Fig. 6C).

Bottom Line: Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein.This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells.Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha).

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.

ABSTRACT

Background: There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression.

Methodology/principal findings: Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1beta increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha).

Conclusions/significance: Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.

Show MeSH
Related in: MedlinePlus