The role of mitochondrial DNA mutations and free radicals in disease and ageing
Open Access
- 7 March 2013
- journal article
- review article
- Published by Wiley in Journal of Internal Medicine
- Vol. 273 (6), 529-543
- https://doi.org/10.1111/joim.12055
Abstract
Considerable efforts have been made to understand the role of oxidative stress in age-related diseases and ageing. The mitochondrial free radical theory of ageing, which proposes that damage to mitochondrial DNA (mtDNA) and other macromolecules caused by the production of reactive oxygen species (ROS) during cellular respiration drives ageing, has for a long time been the central hypothesis in the field. However, in contrast with this theory, evidence from an increasing number of experimental studies has suggested that mtDNA mutations may be generated by replication errors rather than by accumulated oxidative damage. Furthermore, interventions to modulate ROS levels in humans and animal models have not produced consistent results in terms of delaying disease progression and extending lifespan. A number of recent experimental findings strongly question the mitochondrial free radical theory of ageing, leading to the emergence of new theories of how age-associated mitochondrial dysfunction may lead to ageing. These new hypotheses are mainly based on the underlying notion that, despite their deleterious role, ROS are essential signalling molecules that mediate stress responses in general and the stress response to age-dependent damage in particular. This novel view of ROS roles has a clear impact on the interpretation of studies in which antioxidants have been used to treat human age-related diseases commonly linked to oxidative stress.Keywords
This publication has 111 references indexed in Scilit:
- Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signalingCellular Signalling, 2012
- Mitochondrial Genome Instability and ROS Enhance Intestinal Tumorigenesis in APCMin/+ MiceThe American Journal of Pathology, 2012
- The SirT3 Divining Rod Points to Oxidative StressMolecular Cell, 2011
- Fine Tuning Our Cellular Factories: Sirtuins in Mitochondrial BiologyCell Metabolism, 2011
- Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric RestrictionCell, 2010
- Hydroethidine- and MitoSOX-derived red fluorescence is not a reliable indicator of intracellular superoxide formation: Another inconvenient truthFree Radical Biology & Medicine, 2010
- Is the oxidative stress theory of aging dead?Biochimica et Biophysica Acta (BBA) - General Subjects, 2009
- Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase IIIAnnals of Neurology, 2009
- Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21Cell Metabolism, 2007
- The SU.VI.MAX StudyArchives of Internal Medicine, 2004