Abstract
BackgroundThere 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 FindingsHere, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1β 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-1β increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1β-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1β increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor α (ERRα).Conclusions/SignificanceTaken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1β in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.
Highlights
Mitochondria are dynamic organelles whose morphology is regulated by fusion and fission processes
In the present study we demonstrate that mitochondrial dynamics balance can be shifted towards fusion by transcriptional regulation
We show that PGC-1b is a regulator of mitochondrial fusion through its effects of selectively promoting Mitofusin 2 (Mfn2) expression upon coactivation of Estrogen Related Receptor a (ERRa)
Summary
Mitochondria are dynamic organelles whose morphology is regulated by fusion and fission processes. Several genes encoding mitochondrial fusion and fission proteins have been recently identified. Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2) and Optic Atrophy gene 1 (OPA1) are proteins that participate in mitochondrial fusion in mammals [8]. There are no evidences to date that demonstrate the ability of an upstream or transcriptional regulator to shift the balance between mitochondrial fusion and fission events by selective regulation of these proteins. 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
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