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  1. Evaluation Summary:

    This paper explores the under-investigated role of mitochondrial activity and subcellular distribution for alveolar formation by using a variety of transgenic mouse models to delete two specific mitochondrial proteins. The data suggest a new concept for mitochondrial dysfunction driving lung injury and potentially human disease. With some further evidence to support the potential cell-specific role for the observed outcomes and additional mitochondrial assessment, this paper will be of interest to a large group of scientists interested in mitochondrial metabolism in general as well as lung development and disease in particular.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    This is an interesting study focusing on the under-investigated role of mitochondria distribution and function for postnatal lung development in the mice. The study focuses on the impact of deleting two mitochondria related proteins: Tfam, a master regulator of mitochondrial transcription, and Miro1, a protein regulating normal subcellular distribution of mitochondria. Both proteins have been deleted in globally as well as lung epithelial- or mesenchymal-specific in mice and the lungs have been anayzed by histological analysis, immunostainings and PCR. Consistently, a defect in postnatal alveolar formation was found. As a potential mechanisms the author report that the number of myofibroblasts marked by PDGFRA was reduced in the absence of epithelial Tfam and that secretion of PDGF ligand from Tfam- and Miro1-deficient alveolar epithelial cells was compromised, while transcription activity was not altered. While most of the results were largely based on descriptive gene and protein data generated in transgenic mice, myofibrobasts were further isolated from these mouse lungs and subjected to a migration assays. The data suggest a new concept of mechanisms involved in lung injury and potentially human disease, which needs further exploration.

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  3. Reviewer #2 (Public Review):

    The authors in this manuscript present data, showing defection of mitochondrial activity and distribution in both alveolar epithelial cells and mesenchymal cells impairs alveolar formation. The initial rationale of the manuscript is gaining the insight that mitochondria display dynamic distribution during alveolar formation. They demonstrate two different ways through which the defection of mitochondria in alveolar epithelial cells and mesenchymal cells impairs secondary septa formation respectively. Further studies identify mTORC1 pathway as a central player in controlling mitochondrial function during alveolar formation. What is more interesting, authors indicate a connection between mitochondrial function and pathogenesis of COPD/emphysema. Considering that mitochondria is the hub of cellular metabolic network, this manuscript may raise broad attention on mitochondria as well as cellular metabolism as drivers of tissue remodeling.

    It is of interest that authors conducted experiments on various mouse models with defective mitochondria in either alveolar epithelial cells or mesenchymal cells. However, confirmation of the inactivated genes (eg. Tfam, Mirol) and subsequently impaired mitochondrial function is missing. Therefore, the conclusion that loss of mitochondrial activity disrupts alveologenesis is questionable with insufficient mitochondrial function analysis. Additionally, since high expression of β-galactosidase is a feature of senescent cells and Tfam-deficient cells show premature senescence, mouse line of Tfamf/f; Pdgfaex4COIN/+; Sox9Cre/+ can not properly indicates Pdgfa expression.

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  4. Reviewer #3 (Public Review):

    In the manuscript entitled "Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria" Zhang et al. argue that mitochondrial function and spatial distribution within specific cells accounts for secondary septation. Use of transgenic mouse models, in vitro experiments and data from human tissue provides support for the importance of the mitochondria in alveolar epithelium and myofibroblasts. The use of multiple transgenic models to relatively selectively deplete mitochondrial number or function in a cell specific manner is a a strength. These models will be of interest to the broader pulmonary biology community. However, the conclusions of the manuscript would be strengthened further still by evidence demonstrating that alveolarization was not affected by loss of mitochondria in some cell-specific manner. As currently configured, loss of mitochondria in any of the cell types compromised alveolarization. This observation prompts the question of whether constraining energy availability in any cell in the alveolus might result in compromise of alveolarization? For example, does loss of mitochondrial function in endothelial cells in the microcirculation have the same effect? It is important to distinguish between a fundamental cellular process that is required for normal function of any given cell type and one that is especially significant in the cell types emphasized in the present study. Given the close relationship between cellular bioenergetics and cell survival and proliferation, cell-specific interrogation of these properties in the context of altered mitochondrial number or distribution would be important.

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