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Review
. 2013 Oct 3;4(6):364-80.
doi: 10.14336/AD.2013.0400364.

mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences

Sara C Zapico  1 , Douglas H Ubelaker
Affiliations
Review

mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences

Sara C Zapico et al. Aging Dis. .

Abstract

Mitochondria are independent organelles with their own DNA. As a primary function, mitochondria produce the energy for the cell through Oxidative Phosphorylation (OXPHOS) in the Electron Transport Chain (ETC). One of the toxic products of this process is Reactive Oxygen Species (ROS), which can induce oxidative damage in macromolecules like lipids, proteins and DNA. Mitochondrial DNA (mtDNA) is less protected and has fewer reparation mechanisms than nuclear DNA (nDNA), and as such is more exposed to oxidative, mutation-inducing damage. This review analyzes the causes and consequences of mtDNA mutations and their relationship with the aging process. Neurodegenerative diseases, related with the aging, are consequences of mtDNA mutations resulting in a decrease in mitochondrial function. Also described are "mitochondrial diseases", pathologies produced by mtDNA mutations and whose symptoms are related with mitochondrial dysfunction. Finally, mtDNA haplogroups are defined in this review; these groups are important for determination of geographical origin of an individual. Additionally, different haplogroups exhibit variably longevity and risk of certain diseases. mtDNA mutations in aging and haplogroups are of special interest to forensic science research. Therefore this review will help to clarify the key role of mtDNA mutations in these processes and support further research in this area.

Keywords: Aging; Diseases; Electron Transport Chain (ETC); Forensic Sciences; Mitochondrial DNA (mtDNA); Reactive Oxygen Species (ROS).

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Figures

Figure 1.
Figure 1.
Mitochondria structure.
Figure 2.
Figure 2.
Oxidative Phosphorylation (OXPHOS). NADH and FADH2 are produced from the intermediary metabolism of carbohydrates, proteins and fats; and they donate electrons to complex I (NADH-ubiquinone oxidoreductase) and complex II (succinate-ubiquinone oxidoreductase). These electrons are passed sequentially to ubiquinone (coenzyme Q or CoQ) to form ubisemiquinone (CoQH) and then ubiquinol (CoQH2). Ubiquinol transfers its electrons to complex III (ubiquinol-cytochrome c oxidase reductase), which transfers them to cytochrome c. From cytochrome c, the electrons flow to complex IV (cytochrome c oxidase or COX), which donates an electron to oxygen to produce water. The energy liberated by the flow of electrons is used by complexes I, III and IV to pump protons (H−) out of the mitochondrial inner membrane into the intermembrane space. This proton gradient generates the mitochondrial membrane potential that is coupled to ATP synthesis by complex V from ADP (Adenosin diphosphate) and inorganic phosphate (Pi). ATP is released from the mitochondria in exchange for cytosolic ADP using a carrier, adenine nucleotide translocator (ANT).
Figure 3.
Figure 3.
Generation of mitochondrial ROS. Superoxide is produced by complex I on the matrix side of the inner mitochondrial membrane and by complex III on both sides of the inner mitochondrial membrane. It is converted to hydrogen peroxide (H2O2) by the matrix enzyme manganese superoxide dismutase (MnSOD or SOD2) or by the mitochondrial intermembrane space and cytosol enzyme copper/zinc SOD (Cu/ZnSOD or SOD1). Hydrogen peroxide can diffuse into the cytosol and nucleus to activate redox-sensitive signaling. Hydrogen peroxide is detoxified in water by glutathione peroxidase (GPx) in the mitochondria and cytosol. In the presence of reduced transition metals (like Fe2+), hydrogen peroxide is converted to hydroxyl radical (OH.) through the Fenton reaction.
Figure 4.
Figure 4.
Mitochondrial DNA. D-loop is shown in red. The genes that encode the subunits of complex I (ND1–ND6 and ND4L) are shown in green; cytochrome c oxidase (COI–COIII) is shown in purple; cytochrome b of complex III is shown in blue; and the subunits of the ATP synthase (ATPase 6 and 8) are shown in orange. The genes for the two rRNAs (12S and 16S) are shown in pink and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A) are indicated by boxes in yellow. The Origins of Heavy-strand replication (OH) and Light-strand replication (OL) are shown.
Figure 5.
Figure 5.
“Vicious cycle” of mtDNA damage by ROS. ROS can react with mtDNA, inducing mutations. These mutations cause a decrease in the activity of ETC, producing dysfunction in the mitochondria which can lead to cell death.
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