PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension

John J. Ryan, Glenn Marsboom, Yong Hu Fang, Peter T. Toth, Erik Morrow, Nancy Luo, Lin Piao, Zhigang Hong, Kyle Ericson, Hannah J. Zhang, Mei Han, Chad R. Haney, Chin Tu Chen, Willard W. Sharp, Stephen L. Archer*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    159 Scopus citations


    Rationale: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance.The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. Objectives: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), was assessed.MFN2 therapy was tested in PAH PASMC and in models of PAH. Methods: Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo. Measurements and Main Results: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 ± 35 vs. 245 ± 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 ± 0.02 vs. 0.38 ± 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 ± 0.8 vs. 19 ± 1.7%; P < 0.05). Lung vascularity was increased by MFN2. Conclusions: Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.

    Original languageEnglish (US)
    Pages (from-to)865-878
    Number of pages14
    JournalAmerican journal of respiratory and critical care medicine
    Issue number8
    StatePublished - Apr 15 2013


    • Female sex
    • Hypoxia-inducible factor-1 α
    • Mitochondrial fission
    • Optic atrophy 1
    • Peroxisome proliferator-activated receptor gamma coactivator-1 α

    ASJC Scopus subject areas

    • Critical Care and Intensive Care Medicine
    • Pulmonary and Respiratory Medicine


    Dive into the research topics of 'PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension'. Together they form a unique fingerprint.

    Cite this