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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.

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Related in: MedlinePlus

PGC-1β KO mice show a specific decrease in Mfn2 expression in skeletal muscle.Gastrocnemius muscles from 4- or 8-month-old wild-type (WT, black bars) or 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 muscle lysates. Graph represents mean±SEM of Mfn2 levels relative to Porin values (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics (Mfn1, OPA1, Drp1 and Fis1) in total lysates. 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). 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.
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pone-0003613-g005: PGC-1β KO mice show a specific decrease in Mfn2 expression in skeletal muscle.Gastrocnemius muscles from 4- or 8-month-old wild-type (WT, black bars) or 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 muscle lysates. Graph represents mean±SEM of Mfn2 levels relative to Porin values (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics (Mfn1, OPA1, Drp1 and Fis1) in total lysates. 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). 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: We next studied the effects of in vivo ablation of PGC-1β on Mfn2 expression in gastrocnemius muscles. Mfn2 protein levels were reduced by approximately 50% in KO mice (Fig. 5A). Reduction of Mfn2 levels was relatively specific as indicated by the absence of major changes in proteins involved in mitochondrial dynamics, i.e., Mfn1, OPA1, Drp1 and Fis1 (Fig. 5B). Similar results were obtained using mitochondrial fractions (data not shown). Reduced Mfn2 protein expression paralleled lower levels of Mfn2 mRNA (Fig. 5C).


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)

PGC-1β KO mice show a specific decrease in Mfn2 expression in skeletal muscle.Gastrocnemius muscles from 4- or 8-month-old wild-type (WT, black bars) or 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 muscle lysates. Graph represents mean±SEM of Mfn2 levels relative to Porin values (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics (Mfn1, OPA1, Drp1 and Fis1) in total lysates. 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). 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-g005: PGC-1β KO mice show a specific decrease in Mfn2 expression in skeletal muscle.Gastrocnemius muscles from 4- or 8-month-old wild-type (WT, black bars) or 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 muscle lysates. Graph represents mean±SEM of Mfn2 levels relative to Porin values (n = 6 mice per group). *, statistical difference at p<0.01. (B) Abundance of proteins involved in mitochondrial dynamics (Mfn1, OPA1, Drp1 and Fis1) in total lysates. 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). 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: We next studied the effects of in vivo ablation of PGC-1β on Mfn2 expression in gastrocnemius muscles. Mfn2 protein levels were reduced by approximately 50% in KO mice (Fig. 5A). Reduction of Mfn2 levels was relatively specific as indicated by the absence of major changes in proteins involved in mitochondrial dynamics, i.e., Mfn1, OPA1, Drp1 and Fis1 (Fig. 5B). Similar results were obtained using mitochondrial fractions (data not shown). Reduced Mfn2 protein expression paralleled lower levels of Mfn2 mRNA (Fig. 5C).

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