Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death

J Mol Cell Cardiol. 2008 Feb;44(2):411-8. doi: 10.1016/j.yjmcc.2007.10.013. Epub 2007 Dec 11.


Adult rat cardiomyocytes in culture respond to sub-lethal doses of lipopolysaccharides (LPS) by activation of pathways including the production of TNF-alpha and increased apoptosis. We and others have demonstrated a protective phenotype for neonatal rat cardiomyocytes to LPS. Concentrations of LPS far exceeding those necessary to induce TNF-alpha release do not induce apoptosis in the neonatal cells, although these cells are fully capable or inducing apoptosis in response to multiple other stimuli. In neonatal cells, we demonstrate that LPS treatment leads to a loss of mitochondrial membrane potential (Deltapsi) which is temporally associated with an increase in the level of uncoupling protein 3 (UCP3). Cells remain viable with no measurable increase in apoptotic or necrotic cell death. Many markers of mitochondrial biogenesis are also activated. LPS treatment stimulates an increase in the (i) transcription of mitochondrial transcription factor A (Tfam), (ii) nuclear accumulation of redox-sensitive nuclear respiratory factor 1 (NRF-1), and (iii) expression of peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1). We also observed that LPS increased intracellular autophagy. Autophagy was assessed by monitoring the levels of a mammalian protein specifically associated with autophagosomes, microtubule-associated light chain 3 (LC3). Furthermore, inhibition of autophagy in the presence of LPS stimulates markers of apoptosis. Our data suggest that the protective response of neonatal cells to LPS is multi-faceted at the level of the mitochondrion. Viable cells replace dysfunctional mitochondria by mitochondrial biogenesis and the extent of the damage limited by the rapid removal of damaged organelles by the stimulation of autophagy.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Biomarkers / metabolism
  • Blotting, Western
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Glutathione / metabolism
  • Ion Channels / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Lipopolysaccharides / pharmacology*
  • Membrane Potential, Mitochondrial / drug effects
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • Oxidative Stress / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Transcription Factors / metabolism
  • Uncoupling Protein 3


  • Biomarkers
  • Ion Channels
  • LC3 protein, rat
  • Lipopolysaccharides
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Transcription Factors
  • Ucp3 protein, rat
  • Uncoupling Protein 3
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • 3-methyladenine
  • Adenosine Triphosphate
  • L-Lactate Dehydrogenase
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Glutathione
  • Adenine