On 2015 May 07, Tullio Pozzan commented:

We believe that the discrepancy between the data presented in our paper (Filadi et al. PNAS 2015 Apr 28;112(17):E2174-81. doi: 10.1073/pnas.1504880112. Epub 2015 Apr 13.) and those of Schneeberger et al. (Cell. 2013 Sep 26;155(1):172-87. doi: 10.1016/j.cell.2013.09.003) may be only apparent. In particular, Schneeberger et al. demonstrate (Fig 1 D and E) that in mice rendered obese by high fat diet there is a major reduction in mitochondria/ER contacts in POMC neurons and an early reduction in Mfn2 expression. They then show that mice with a selective KO of Mfn2 in POMC neurons become obese and show, at this stage, a reduction in mitochondria-ER contacts. Given that Schneeberger et al, investigated the reduction in ER-mitochondria close contacts only in 18 week old mice (i.e. when obesity is evident and not after a short high fat diet treatment (4 days), when Mfn2 reduction is already visible, but obesity is not), it is not possible to distinguish whether the change in ER-mitochondria close contacts is a consequence of Mfn2 reduction or of obesity (and/or of the very complex alteration of metabolism occurring in those conditions). In other words, the data presented in the very elegant paper by Schneeberger et al. do not clarify whether the reduction in ER-mitochondria close contacts is a direct consequence of Mfn2-KO in POMC neurons or an indirect effect of different altered pathways that lead to obesity and metabolism alteration. On the contrary, in the experiment by Filadi et al., in cultured MEF cells, acute down-regulation of Mfn2 results in a rapid increase of ER-mitochondria tethering. A similar result, i.e. increase in ER-mitochondria close contacts, has been also observed in a stable Mfn2 ablated cell line (and rescued by Mfn2 re-expression) independently by Filadi et al and by Cosson et al. Thus, in our opinion the role played by Mfn2 in different metabolic pathways leading to obesity is multiple and cell type-specific (see also the paper by Dietrich et al., in the same Cell issue) and not causally linked to its structural function on ER-mitochondria tethering, as actually pointed out by the same Authors suggesting a main role for Mfn2 in POMC neurons as an ER-stress modulating molecule.

On 2015 May 07, Tullio Pozzan commented:

We believe that the discrepancy between the data presented in our paper (Filadi et al. PNAS 2015 Apr 28;112(17):E2174-81. doi: 10.1073/pnas.1504880112. Epub 2015 Apr 13.) and those of Schneeberger et al. (Cell. 2013 Sep 26;155(1):172-87. doi: 10.1016/j.cell.2013.09.003) may be only apparent. In particular, Schneeberger et al. demonstrate (Fig 1 D and E) that in mice rendered obese by high fat diet there is a major reduction in mitochondria/ER contacts in POMC neurons and an early reduction in Mfn2 expression. They then show that mice with a selective KO of Mfn2 in POMC neurons become obese and show, at this stage, a reduction in mitochondria-ER contacts. Given that Schneeberger et al, investigated the reduction in ER-mitochondria close contacts only in 18 week old mice (i.e. when obesity is evident and not after a short high fat diet treatment (4 days), when Mfn2 reduction is already visible, but obesity is not), it is not possible to distinguish whether the change in ER-mitochondria close contacts is a consequence of Mfn2 reduction or of obesity (and/or of the very complex alteration of metabolism occurring in those conditions). In other words, the data presented in the very elegant paper by Schneeberger et al. do not clarify whether the reduction in ER-mitochondria close contacts is a direct consequence of Mfn2-KO in POMC neurons or an indirect effect of different altered pathways that lead to obesity and metabolism alteration. On the contrary, in the experiment by Filadi et al., in cultured MEF cells, acute down-regulation of Mfn2 results in a rapid increase of ER-mitochondria tethering. A similar result, i.e. increase in ER-mitochondria close contacts, has been also observed in a stable Mfn2 ablated cell line (and rescued by Mfn2 re-expression) independently by Filadi et al and by Cosson et al. Thus, in our opinion the role played by Mfn2 in different metabolic pathways leading to obesity is multiple and cell type-specific (see also the paper by Dietrich et al., in the same Cell issue) and not causally linked to its structural function on ER-mitochondria tethering, as actually pointed out by the same Authors suggesting a main role for Mfn2 in POMC neurons as an ER-stress modulating molecule.