TNFa induces mitochondrial fragmentation and biogenesis in human airway smooth muscle

Philippe Delmotte, Natalia Marin Mathieu, Gary C. Sieck

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

In human airway smooth muscle (hASM), mitochondrial volume density is greater in asthmatic patients compared with normal controls. There is also an increase in mitochondrial fragmentation in hASM of moderate asthmatics associated with an increase in dynamin-related protein 1 (Drp1) and a decrease in mitofusin 2 (Mfn2) expression, mitochondrial fission, and fusion proteins, respectively. Proinflammatory cytokines such TNFa contribute to hASM hyperreactivity and cell proliferation associated with asthma. However, the involvement of proinflammatory cytokines in mitochondrial remodeling is not clearly established. In nonasthmatic hASM cells, mitochondria were labeled using MitoTracker Red and imaged in three dimensions using a confocal microscope. After 24-h TNFa exposure, mitochondria in hASM cells were more fragmented, evidenced by decreased form factor and aspect ratio and increased sphericity. Associated with increased mitochondrial fragmentation, Drp1 expression increased while Mfn2 expression was reduced. TNFa also increased mitochondrial biogenesis in hASM cells reflected by increased peroxisome proliferator-activated receptor-c coactivator 1a expression and increased mitochondrial DNA copy number. Associated with mitochondrial biogenesis, TNFa exposure also increased mitochondrial volume density and porin expression, resulting in an increase in maximum O2 consumption rate. However, when normalized for mitochondrial volume density, O2 consumption rate per mitochondrion was reduced by TNFa exposure. Associated with mitochondrial fragmentation and biogenesis, TNFa also increased hASM cell proliferation, an effect mimicked by siRNA knockdown of Mfn2 expression and mitigated by Mfn2 overexpression. The results of this study support our hypothesis that in hASM cells exposed to TNFa mitochondria are more fragmented, with an increase in mitochondrial biogenesis and mitochondrial volume density resulting in reduced O2 consumption rate per mitochondrion.

Original languageEnglish (US)
Pages (from-to)L137-L151
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume320
Issue number1
DOIs
StatePublished - 2021

Keywords

  • Airway smooth muscle
  • Fission
  • Fusion
  • Imaging
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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