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Review
. 2013 Jun;273(6):529-43.
doi: 10.1111/joim.12055. Epub 2013 Mar 7.

The role of mitochondrial DNA mutations and free radicals in disease and ageing

M Lagouge  1 , N-G Larsson
Affiliations
Free PMC article
Review

The role of mitochondrial DNA mutations and free radicals in disease and ageing

M Lagouge et al. J Intern Med. 2013 Jun.
Free PMC article

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.

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Figures

Fig. 1
Fig. 1
Schematic representation of the mitochondrial free radical theory of ageing. Reactive oxygen species (ROS) are normal by-products of mitochondrial function that progressively damage the constituents of mitochondria, inducing mitochondrial dysfunction and increased ROS production through a vicious cycle, leading ultimately to cellular dysfunction and ageing.
Fig. 2
Fig. 2
Organization of the mammalian mtDNA. The mammalian mitochondrial DNA (mtDNA) is a double-stranded circular molecule. The two strands are denoted the heavy (H) and the light (L) strands. The noncoding D-loop region contains the promoters for the H and L strands (HSP and LSP) as well as the origin of replication of the leading strand of mtDNA (OH). Transcription from HSP produces two rRNAs (12S and 16S rRNA), 10 mRNAs (the monocistronic ND1–3, ND5, Cyt b and COI–III mRNAs, and the biscistronic ND4/ND4L and ATP6/ATP8 mRNAS) and 14 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2 and T). Transcription from LSP produces one mRNA (ND6) and eight tRNAs (P, E, S2, Y, C, N, A and Q). Reproduced from .
Fig. 3
Fig. 3
Mitotic segregation of mtDNA. A single mutational event within a mitochondrial DNA (mtDNA) molecule creates heteroplasmy in a cell. Mutated mtDNA molecules are shown in red and normal mtDNA molecules in green. There is no synchronization between mtDNA replication and cell division, which means that a particular mtDNA molecule, mutated or not, may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA molecules. Accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.
Fig. 4
Fig. 4
The oxidative phosphorylation system. The respiratory chain, composed of four complexes (I to IV), transfers electrons (e-) in a stepwise manner until they finally reduce O2 to form H2O. Electron transfer is coupled to a vectorial proton translocation outside the matrix space through three of the four complexes (I, III and IV). Protons accumulate and create an electrochemical gradient across the inner mitochondrial membrane. This osmotic energy is used to drive ATP synthesis as the protons re-enter the mitochondrial matrix through ATP synthase (the complexes are not drawn to scale). Adapted from .
Fig. 5
Fig. 5
Reactive oxygen species (ROS) detoxification enzymes. The cell is equipped with a variety of defence mechanisms to scavenge ROS. Superoxide dismutases catalyse the dismutation of superoxide into oxygen and hydrogen peroxide. Catalase reacts with the hydrogen peroxide to catalyse the formation of water and oxygen. Glutathione peroxidase reduces hydrogen peroxide. GSH stands for reduced glutathione whereas GSSG stands for oxidized glutathione.
Fig. 6
Fig. 6
The gradual reactive oxygen species (ROS) response hypothesis. Reactive oxygen species-independent age-related damage induces the production of ROS as part of a stress-response defence pathway (left). At this stage, toxicity is well controlled by the antioxidant system and is therefore not deleterious. ROS-independent damage accumulates with age and induces a progressive increase in ROS generation as the cell attempts to increase its stress response (right). The antioxidant system is overwhelmed by the increased amount of ROS, and ROS-induced damage will occur and contribute to the total increase in age-associated damage (right). ROS thus have a dual role in ageing: initially ROS promote signalling to prevent damage accumulation; later, ROS contribute to damage creation. Adapted from .
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