Article activity feed

  1. eLife assessment

    This manuscript describes a mouse model of a human mitofusin 2- related lipodystrophy, generated by knockin of Mfn2 R707W, and reports data suggesting adipocyte-specific effects involving the integrated stress response, mTorc signaling, and epithelial-mesenchymal transition pathways. The data will be important for understanding how mitochondria can be affected in tissue-specific manner to contribute to metabolic disease.

  2. Reviewer #1 (Public Review):

    The article by Mann et al. describes a knockin (KI) mouse model of mitofusin 2- related lipodystrophy, in mice carrying MFN2 R707W. The mice recapitulate some but not all aspects of the human phenotype, as summarized in Table 2. The phenotypic characterization is extensive and is generally well done. There was an adipose-specific alteration of mitochondrial morphology, accompanied by activation of the integrated stress response and reduced adipokine secretion. These findings are consistent with the human phenotype. The alteration in fat distribution that is present in humans with this mutation was not observed, and the mice did not have the insulin resistance seen in humans. The transcriptome analyses revealed a reduced epithelial-mesenchymal transition (EMT) in the KI mice, suggesting possible involvement of TGF-beta related pathways. There was also upregulation of the mTorc signaling pathway, suggesting that a possible therapeutic approach in humans may involve the mTORC1 inhibitor sirolimus. The reason for the largely adipose -specific effect of the mutation remains unexplained. As well, the hypothesis that changes in EMT pathways reflect altered activity of TGF-beta pathways must remain somewhat speculative at this point. Notwithstanding these weaknesses, the manuscript provides an important advance in understanding this lipodystrophy (and potentially other lipodystrophies), and the model that has been generated will enable further studies to further characterize the pathophysiology.

  3. Reviewer #2 (Public Review):

    This study generated a valuable preclinical model of patients with Mfn2-related lipodistrophy (R707W). Such a mouse model enables the understanding the pathogenic mechanism causing this lipodistrophy and testing specific therapeutic approaches for these patients.

    The strengths are the thorough phenotypic characterization of the mice and the clear decrease in circulating leptin and adiponectin levels in the absence of changes in fat mass observed in Mfn2 R707W/R707W mice. This partially recapitulates one of the key phenotypes of human patients with these mutations.

    The major weakness is the conclusion that the integrated stress response is activated in white adipose tissue is not supported by the data and the phenotype. The ISR caused by primary insults to mitochondria was defined as a response that decreases the translation of mitochondrial proteins, thus decreasing mitochondrial respiratory function via ATF4 without engaging ATF5 (Quiros et al., JCB 2016). In addition, the increase in ATF4 caused by phosphorylation of eif2alpha is in ATF4 translation and translocation to the nucleus, not in ATF4 transcription. It is a possibility that it is a selective increase in ER stress that is responsible for defective leptin secretion, as Mfn2 R707W/R707W adipose tissue shows no mitigation of mitochondrial function as expected from ATF4-ISR activation.

  4. Reviewer #3 (Public Review):

    Mann and colleagues have generated a knock-in mouse model carrying a recently identified mutation in the Mfn2 gene that leads to a syndrome of severe upper body adipose overgrowth in humans (Mfn2R707W). The goal was to gain a better mechanistic understanding on how this mutation leads to such a dramatic phenotype in humans. The authors consistently demonstrate how the knock-in mutation leads to abnormalities in mitochondrial shape, mtDNA content, as well as in the abundance of some mitochondrial proteins, most notably in brown adipose tissue. The authors detect some stress response signatures, which could explain the decreased leptin and adiponectin levels observed in the knockin mice.

    The authors have to be praised for their effort in trying to provide mechanistic insights to such a rare condition. This work constitutes a real tour de force in the characterization of Mfn2R707W mice. The path, however, was full of surprises. On one side, the knockin mouse model fails to recapitulate multiple aspects of the human syndrome. This is, of course, beyond the control of the researchers, but somehow tells us that there are some elements missing in our understanding of the effects of this Mfn2 mutation at the cellular level (not just organismal), and on why it impacts so much adipose tissues. A second layer of complexity is that the authors find an interesting connection between Mfn2R707W, the integrated stress response and a severe decrease in the expression of leptin and adiponectin. However, whether these elements have any causal role in the human syndrome or in the phenotypes observed in the mice, remains an open question.