Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5507121 | Biochimica et Biophysica Acta (BBA) - Bioenergetics | 2017 | 72 Pages |
Abstract
Mitochondria exhibit suppressed ATP production, membrane potential (âΨmt) polarization and reactive oxygen species (ROS) bursts during some cellular metabolic transitions. Although mitochondrial ROS release is influenced by âΨmt 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, âΨmt and respiration. We uncovered a previously unknown spontaneous ROS spike - termed mitochondrial transition ROS spike (mTRS) - associated with re-polarization of âΨmt 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 âΨmt-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.
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Authors
Mahmoud S. Sharaf, Don Stevens, Collins Kamunde,