Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis
Luis R. Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H. Cooper, Apoorva Babu, Aaron I. Weiner, Andrew E. Vaughan, Zoltan Arany, Orian S. Shirihai, Darrell N. Kotton, Michael F. Beers
Luis R. Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H. Cooper, Apoorva Babu, Aaron I. Weiner, Andrew E. Vaughan, Zoltan Arany, Orian S. Shirihai, Darrell N. Kotton, Michael F. Beers
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Research Article Metabolism Pulmonology

Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis

Abstract

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell–exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell–derived (iPSC-derived) AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 cell self-renewal and accumulation of transitional epithelial cells. We identify deficient AMPK signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.

Authors

Luis R. Rodríguez, Konstantinos-Dionysios Alysandratos, Jeremy Katzen, Aditi Murthy, Willy Roque Barboza, Yaniv Tomer, Sarah Bui, Rebeca Acín-Pérez, Anton Petcherski, Kasey Minakin, Paige Carson, Swati Iyer, Katrina Chavez, Charlotte H. Cooper, Apoorva Babu, Aaron I. Weiner, Andrew E. Vaughan, Zoltan Arany, Orian S. Shirihai, Darrell N. Kotton, Michael F. Beers

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Figure 7

In vivo rescue of the SftpcI73T fibrotic phenotype via metformin intervention.

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In vivo rescue of the SftpcI73T fibrotic phenotype via metformin interve...
(A) Study design for metformin intervention in the SftpcI73T fibrosis mouse model. Metformin (150 mg/kg) or vehicle control was administered intraperitoneal (i.p.) daily on weekdays starting at 12 days after tamoxifen induction (n = 20 mice per group). (B) At 28 days, mortality was significantly (P = 0.0199) reduced in metformin-treated mice. (C) Representative Masson’s trichrome staining of SftpcI73T mouse lungs treated with either metformin or vehicle control and collected at 28 days after tamoxifen induction. (D and E) Static lung compliance, measured by SCIREQ Flexivent, increased significantly in metformin-treated mice compared with vehicle control (mean±SEM; n = 14 mice for vehicle group and n = 12 for WT and metformin groups). (F and G) Markers of inflammation and lung injury in the bronchoalveolar lavage fluid (BALF) collected from mice at 28 days after tamoxifen were significantly reduced in metformin-treated mice (mean±SEM; n = 12 mice per group). (H) OCR measurement and quantification in AT2 cells isolated from WT and SftpcI73T mice at 28 days after in vivo tamoxifen induction. AT2 cells were seeded overnight before respirometry was performed (mean±SEM; n = 8 mice per group). (I) ELISA quantification of CCL17 and CCL2 concentrations in BALF of WT and SftpcI73T mice at 28 days after in vivo tamoxifen induction (mean±SEM; n = 4 WT, 9 vehicle, and 10 I73T mice). *P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.00005 by ordinary 1-way ANOVA.