ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP

J Biol Chem. 2020 Jan 31;295(5):1369-1384. doi: 10.1074/jbc.RA119.011244. Epub 2019 Dec 23.


Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.

Keywords: ATP; angiotensin-converting enzyme (ACE); electron transport chain; macrophage; mitochondria; neutrophil; oxidative metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Citric Acid Cycle
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Electron Transport Complex I / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Myeloid Cells / metabolism*
  • Neutrophils / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Up-Regulation


  • Angiotensin-Converting Enzyme Inhibitors
  • Membrane Proteins
  • NDUFB8 protein, mouse
  • Adenosine Triphosphate
  • Ptgs2 protein, mouse
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Ptgs1 protein, mouse
  • Peptidyl-Dipeptidase A
  • ATP5A1 protein, mouse
  • Mitochondrial Proton-Translocating ATPases
  • Electron Transport Complex I