Sharaf 2017 Biochim Biophys Acta

Sharaf MS, Stevens D, Kamunde C (2017) Mitochondrial transition ROS spike (mTRS) results from coordinated activities of complex I and nicotinamide nucleotide transhydrogenase. Biochim Biophys Acta 1858:955-65.

» PMID: 28866380;»

Sharaf MS, Stevens D, Kamunde C (2017) Biochim Biophys Acta

Abstract: Mitochondria exhibit suppressed ATP production, membrane potential (∆Ψmt) polarization and reactive oxygen species (ROS) bursts during some cellular metabolic transitions. Although mitochondrial ROS release is influenced by ∆Ψmt and respiratory state, the relationship between these properties remains controversial primarily because they have not been measured simultaneously. We developed a multiparametric method for probing mitochondrial function that allowed precise characterization of the temporal relationship between ROS, ∆Ψmt and respiration. We uncovered a previously unknown spontaneous ROS spike - termed mitochondrial transition ROS spike (mTRS) - associated with re-polarization of ∆Ψmt that occurs at the transition between mitochondrial energy states. Pharmacological inhibition of complex CI (CI), nicotinamide nucleotide transhydrogenase (NNT) and antioxidant system significantly decreased the ability of mitochondria to exhibit mTRS. NADH levels followed a similar trend to that of ROS during the mTRS, providing a link between CI and NNT in mTRS regulation. We show that (i) mTRS is enhanced by simultaneous activation of CI and complex II (CII); (ii) CI is the principal origin of mTRS; (iii) NNT regulates mTRS via NADH- and ∆Ψmt-dependent mechanisms; (iv) mTRS is not a pH spike; and (v), mTRS changes in amplitude under stress conditions and its occurrence can be a signature of mitochondrial health. Collectively, we uncovered and characterized the biophysical properties and mechanisms of mTRS, and propose it as a potential diagnostic tool for CI-related dysfunctions, and as a biomarker of mitochondrial functional integrity.

Copyright © 2017 Elsevier B.V. All rights reserved. • Keywords: Glutathione, Membrane potential, NNT, ROS, Thioredoxin, mTRS, Amplex Red • Bioblast editor: Kandolf G • O2k-Network Lab: CA Charlottetown Kamunde C

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Labels: MiParea: Respiration, mt-Membrane, Comparative MiP;environmental MiP, Pharmacology;toxicology 

Stress:Oxidative stress;RONS  Organism: Mouse, Fishes  Tissue;cell: Heart, Liver  Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer, TPP 

2017-09, AmR, O2k-brief