Mitochondrial reactive oxygen species: the effects of mitochondrial ascorbic acid vs untargeted and mitochondria-targeted antioxidants

Abstract

Premise

Mitochondria represent critical sites for reactive oxygen species (ROS) production, which dependent on concentration is responsible for the regulation of both physiological and pathological processes.

Purpose

Antioxidants in mitochondria regulate the redox balance, prevent mitochondrial damage and dysfunction and maintain a physiological ROS-dependent signaling. The aim of the present review is to provide critical elements for addressing this issue in the context of various pharmacological approaches using antioxidants targeted or non-targeted to mitochondria. Furthermore, this review focuses on the mitochondrial antioxidant effects of ascorbic acid (AA), providing clues on the complexities associated with the cellular uptake and subcellular distribution of the vitamin.

Conclusions

Antioxidants that are not specifically targeted to mitochondria fail to accumulate in significant amounts in critical sites of mitochondrial ROS production and may eventually interfere with the ensuing physiological signaling. Mitochondria-targeted antioxidants are more effective, but are expected to interfere with the mitochondrial ROS-dependent physiologic signaling. AA promotes multiple beneficial effects in mitochondria. The complex regulation of vitamin C uptake in these organelles likely contributes to its versatile antioxidant response, thereby providing a central role to the vitamin for adequate control of mitochondrial dysfunction associated with increased mitochondrial ROS production.

Keywords:

• Mitochondrial ROS
• mitochondrial antioxidants
• ascorbic acid
• mitochondrial transport of ascorbic acid

Acknowledgments

This article is dedicated to the memory of Raymond E. Meyn: He will be missed but never forgotten by his Italian friends.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by a grant from the Ministero dell'Istruzione, dell'Università e della Ricerca, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, 2017, [Grant number: 2017FJSM9S].

Notes on contributors

Mara Fiorani

Mara Fiorani, PhD, is an Assistant Professor of Biochemistry at the Department of Biomolecular Sciences of the University of Urbino Carlo Bo (Italy). She is presently working on Vitamin C transport mechanisms in cells and in specific sub-cellular compartments. Her major interest is to understand the relevance of the SVCT2-dependent mitochondrial transport of the reduced form of the vitamin. A second field of interest is on the mechanisms of ROS formation, in particular in the mitochondrial compartment, responsible for the deleterious effects mediated by arsenite.

Andrea Guidarelli

Andrea Guidarelli is an Assistant Professor of Pharmacology at the Department of Biomolecular Sciences of the University of Urbino Carlo Bo (Italy). He focuses on studying the molecular mechanisms whereby toxic compounds and inflammatory mediators induce mitochondrial superoxide formation and downstream signalling events leading to apoptosis. His is currently interested on the effects induced by trivalent arsenic in both the mitochondria and the endoplasmic reticulum.

Orazio Cantoni

Orazio Cantoni is Professor of Pharmacology and Head of the Department of Biomolecular Sciences at the University of Urbino Carlo Bo (Italy). His long-term research focus was on the biological effects of metal compounds, reactive oxygen/nitrogen species and other toxins, associated with the triggering of cyto- and geno-toxic responses. His current interests include investigating how specific cellular systems can be predictive of tissue specific effects resulting in the mitochondrial/extramitochondrial superoxide formation induced by specific agents, in particular arsenite.