In the present study we demonstrate that mitochondrial dynamics balance can be shifted towards fusion by transcriptional regulation. More specifically, we show that PGC-1β is a regulator of mitochondrial fusion through its effects of selectively promoting Mfn2 expression upon coactivation of ERRα. This new role of PGC-1β in mitochondrial physiology has been demonstrated using both in vitro (muscle cells) and in vivo (PGC-1β-ablated mice) approaches. Firstly, we have shown that PGC-1β overexpression in muscle cells regulates mitochondrial dynamics through a mechanism that involves the preferential induction of Mfn2 expression, among other mitochondrial dynamics effectors such as Mfn1, OPA1, Drp1 and Fis1. Furthermore, PGC-1β gain-of-function results in an elongation of mitochondrial tubules, which is linked to an increased mitochondrial fusion. Importantly, the effects of PGC-1β promoting mitochondrial elongation are not observed in Mfn2-ablated cells, thereby demonstrating that Mfn2 activity is essential for PGC-1β-mediated changes in mitochondrial dynamics.
The relevance of these observations is confirmed by our in vivo data showing that PGC-1β KO mice have a specific reduction of Mfn2 expression in skeletal muscle whereas Mfn1, OPA1, Drp1 and Fis1 levels are maintained. In fact, this preferential regulation of Mfn2 protein levels could explain the reduction in mitochondrial volume, without changes in mitochondria number, observed in liver and muscle from PGC-1β loss-of-function mice 
. We propose that Mfn2-impaired function in PGC-1β KO mice prevents a normal rate of mitochondrial fusion while physiological mitochondrial fission events remain unaffected, thereby resulting in smaller mitochondria as previously reported for Mfn2 KO or antisense cells 
Several lines of evidence demonstrate the relevance of maintaining a proper balance between fusion and fission processes for the specific mitochondrial activity required by distinct cell types 
. In this regard, PGC-1β expression is higher in tissues with marked mitochondrial activity (such as liver, muscle and heart), a similar pattern to that reported for Mfn2 
. In addition, we have found that PGC-1β regulates Mfn2 expression in liver, skeletal muscle and heart, as PGC-1β KO mice show a marked decrease in Mfn2 in those tissues. The correlational data mentioned before together with the observations obtained in skeletal muscle, heart and liver from PGC-1β KO mice indicate that PGC-1β controls basal expression of Mfn2 in these tissues.
On the basis of these observations, we propose that increased mitochondrial fusion caused by PGC-1β-induced Mfn2 contributes to a fully optimal mitochondrial activity in muscle and liver tissues, which may be defective in skeletal muscle of type 2 diabetic patients. Furthermore, we propose that PGC-1β controls basal mitochondrial fusion in skeletal muscle, whereas PGC-1α would probably control mitochondrial fusion in high energy expenditure situations, such as cold-exposure or exercise, conditions which largely induce Mfn2 expression 
. This is supported by the fact that PGC-1β expression is higher than PGC-1α expression in skeletal muscle under basal conditions and by the lack of a decrease in mitochondrial size in PGC-1α KO mice 
. In keeping with this proposal, our data permit to explain the observation of a defective mitochondrial respiration found in muscle strips but not in isolated mitochondria from PGC-1β KO mice under basal conditions 
. In isolated mitochondria, the integrity of the mitochondrial network and dynamics inside the cell is not maintained and therefore defects in mitochondrial activity secondary to abnormal mitochondrial dynamics are not detectable.
Here, we have also examined the mechanism by which PGC-1β induces Mfn2 transcription, and have identified ERRα as the key transcription factor coactivated by PGC-1β on the Mfn2 promoter. The effect of ERRα and PGC-1β occurred at the level of box 2 (located in the −459/−352 promoter region), although PGC-1β also displayed additional stimulatory actions on the Mfn2 promoter. The same box 2 region is the major component required for PGC-1α activation of the Mfn2 promoter 
. On the basis of these data, we conclude that PGC-1α and PGC-1β display a common mechanism of activation of the Mfn2 promoter, through nuclear receptor ERRα. However, despite using the same response elements, decreased expression of Mfn2 induced by genetic ablation of PGC-1β in mice cannot be counteracted by PGC-1α action, as shown in liver, heart and skeletal muscle of PGC-1β KO mice, in which Mfn2 expression is decreased, probably due to the low expression of PGC-1α under basal conditions.
In summary, we provide evidence that mitochondrial dynamics balance is selectively controlled by a transcriptional regulator, unravelling an upstream mediator of mitochondrial fusion. Furthermore, we also provide evidence of a novel role of PGC-1β in mitochondrial physiology. Given the crosstalk between mitochondrial activity and dynamics, together with reduced Mfn2 and PGC-1β expression in type 2 diabetes, we conclude that the pathway reported here is not only relevant for the thorough explanation of mitochondrial dynamics regulation and the overall mitochondrial effects of PGC-1β, but also may provide the basis for the correct understanding of the alterations of mitochondrial metabolism associated with type 2 diabetes.