Mitochondrial respiration and ROS emission during β-oxidation in the heart: An experimental-computational study

Sonia Cortassa, Steven J. Sollott, Miguel A. Aon

Research output: Contribution to journalArticle

Abstract

Lipids are main fuels for cellular energy and mitochondria their major oxidation site. Yet unknown is to what extent the fuel role of lipids is influenced by their uncoupling effects, and how this affects mitochondrial energetics, redox balance and the emission of reactive oxygen species (ROS). Employing a combined experimental-computational approach, we comparatively analyze β-oxidation of palmitoyl CoA (PCoA) in isolated heart mitochondria from Sham and streptozotocin (STZ)-induced type 1 diabetic (T1DM) guinea pigs (GPs). Parallel high throughput measurements of the rates of oxygen consumption (VO2) and hydrogen peroxide (H2O2) emission as a function of PCoA concentration, in the presence of L-carnitine and malate, were performed. We found that PCoA concentration < 200 nmol/mg mito protein resulted in low H2O2emission flux, increasing thereafter in Sham and T1DM GPs under both states 4 and 3 respiration with diabetic mitochondria releasing higher amounts of ROS. Respiratory uncoupling and ROS excess occurred at PCoA > 600 nmol/mg mito prot, in both control and diabetic animals. Also, for the first time, we show that an integrated two compartment mitochondrial model of β-oxidation of long-chain fatty acids and main energy-redox processes is able to simulate the relationship between VO2and H2O2emission as a function of lipid concentration. Model and experimental results indicate that PCoA oxidation and its concentration-dependent uncoupling effect, together with a partial lipid-dependent decrease in the rate of superoxide generation, modulate H2O2emission as a function of VO2. Results indicate that keeping low levels of intracellular lipid is crucial for mitochondria and cells to maintain ROS within physiological levels compatible with signaling and reliable energy supply.

Original languageEnglish (US)
Article numbere1005588
JournalPLoS Computational Biology
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Fingerprint

Reactive Oxygen Species
Palmitoyl Coenzyme A
Respiration
Lipids
Oxidation
breathing
reactive oxygen species
respiration
lipid
heart
Mitochondria
oxidation
mitochondrion
Oxygen
lipids
mitochondria
Oxidation-Reduction
energy
Energy
Compartment Model

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

Mitochondrial respiration and ROS emission during β-oxidation in the heart : An experimental-computational study. / Cortassa, Sonia; Sollott, Steven J.; Aon, Miguel A.

In: PLoS Computational Biology, Vol. 13, No. 6, e1005588, 01.06.2017.

Research output: Contribution to journalArticle

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