tetano
Editor, Senior Moderator
Am J Respir Cell Mol Biol
. 2022 Apr 20.
doi: 10.1165/rcmb.2021-0512OC. Online ahead of print.
CDP-choline Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice
Lauren M Doolittle[SUP] 1 [/SUP], Katherine Binzel[SUP] 2 [/SUP], Katherine E Nolan[SUP] 3 [/SUP], Kelsey Craig[SUP] 3 [/SUP], Lucia E Rosas[SUP] 3 [/SUP], Matthew C Bernier[SUP] 4 [/SUP], Lisa M Joseph[SUP] 3 [/SUP], Parker S Woods[SUP] 3 [/SUP], Michael V Knopp[SUP] 2 [/SUP], Ian C Davis[SUP] 5 [/SUP]
Affiliations
Abstract
Development of ARDS in influenza A virus (IAV)-infected mice is associated with inhibition of alveolar type II (ATII) epithelial cell de novo phosphatidylcholine synthesis and administration of the phosphatidylcholine precursor CDP-choline attenuates IAV-induced ARDS in mice. We hypothesized inhibition of phosphatidylcholine synthesis would also impact the function of ATII cell mitochondria. To test this hypothesis, adult C57BL/6 mice of both sexes were inoculated intranasally with 10,000 p.f.u./mouse influenza A/WSN/33 (H1N1). Controls were mock-infected with virus diluent. Mice were treated with saline vehicle or CDP-choline (100 μg/mouse, i.p.) once daily from 1-5 days post-inoculation (dpi). ATII cells were isolated by a standard lung digestion protocol at 6 dpi for analysis of mitochondrial function. IAV infection increased uptake of the glucose analog 18F-FDG by the lungs and caused a switch from oxidative phosphorylation to aerobic glycolysis as a primary means of ATII cell ATP synthesis by 6 dpi. Infection also induced ATII cell mitochondrial depolarization and shrinkage, upregulation of PGC-1α, decreased cardiolipin content, and reduced expression of mitofusin 1, OPA1, DRP1, Complexes I and IV of the electron transport chain, and enzymes involved in cardiolipin synthesis. Daily CDP-choline treatment prevented the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis resulting from IAV infection but did not fully reverse the glycolytic shift. CDP-choline also did not prevent the alterations in mitochondrial protein expression resulting from infection. Taken together, our data show ATII cell mitochondrial dysfunction following IAV infection results from impaired de novo phospholipid synthesis, but the glycolytic shift does not.
Keywords: Cardiolipin; Glycolysis; Oxidative phosphorylation; Phospholipids.
. 2022 Apr 20.
doi: 10.1165/rcmb.2021-0512OC. Online ahead of print.
CDP-choline Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice
Lauren M Doolittle[SUP] 1 [/SUP], Katherine Binzel[SUP] 2 [/SUP], Katherine E Nolan[SUP] 3 [/SUP], Kelsey Craig[SUP] 3 [/SUP], Lucia E Rosas[SUP] 3 [/SUP], Matthew C Bernier[SUP] 4 [/SUP], Lisa M Joseph[SUP] 3 [/SUP], Parker S Woods[SUP] 3 [/SUP], Michael V Knopp[SUP] 2 [/SUP], Ian C Davis[SUP] 5 [/SUP]
Affiliations
- PMID: 35442170
- DOI: 10.1165/rcmb.2021-0512OC
Abstract
Development of ARDS in influenza A virus (IAV)-infected mice is associated with inhibition of alveolar type II (ATII) epithelial cell de novo phosphatidylcholine synthesis and administration of the phosphatidylcholine precursor CDP-choline attenuates IAV-induced ARDS in mice. We hypothesized inhibition of phosphatidylcholine synthesis would also impact the function of ATII cell mitochondria. To test this hypothesis, adult C57BL/6 mice of both sexes were inoculated intranasally with 10,000 p.f.u./mouse influenza A/WSN/33 (H1N1). Controls were mock-infected with virus diluent. Mice were treated with saline vehicle or CDP-choline (100 μg/mouse, i.p.) once daily from 1-5 days post-inoculation (dpi). ATII cells were isolated by a standard lung digestion protocol at 6 dpi for analysis of mitochondrial function. IAV infection increased uptake of the glucose analog 18F-FDG by the lungs and caused a switch from oxidative phosphorylation to aerobic glycolysis as a primary means of ATII cell ATP synthesis by 6 dpi. Infection also induced ATII cell mitochondrial depolarization and shrinkage, upregulation of PGC-1α, decreased cardiolipin content, and reduced expression of mitofusin 1, OPA1, DRP1, Complexes I and IV of the electron transport chain, and enzymes involved in cardiolipin synthesis. Daily CDP-choline treatment prevented the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis resulting from IAV infection but did not fully reverse the glycolytic shift. CDP-choline also did not prevent the alterations in mitochondrial protein expression resulting from infection. Taken together, our data show ATII cell mitochondrial dysfunction following IAV infection results from impaired de novo phospholipid synthesis, but the glycolytic shift does not.
Keywords: Cardiolipin; Glycolysis; Oxidative phosphorylation; Phospholipids.