Mammalian Mitochondria and Aging: An Update Timo E.S. Kauppila, Johanna H.K. Kauppila, Nils-Göran Larsson  Cell Metabolism  Volume 25, Issue 1, Pages 57-71 (January 2017) DOI: 10.1016/j.cmet.2016.09.017 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Clonal Expansion of Mutated mtDNA Molecules Can Lead to Mitochondrial Dysfunction or Can Be Rescued by Compensatory Biogenesis Mitochondrial point mutations that occur early in life can clonally expand to cause mitochondrial dysfunction. This dysfunction can be compensated for by an increase in mitochondrial mass via biogenesis. However, the increase in mitochondrial mass can either increase or decrease the relative level of the dysfunctional mtDNA, leading to either rescue of the dysfunction or continuous biogenesis and cell death (green, functional mitochondria; red, dysfunctional mitochondria). The gauge indicates either deficient energy supply (red zone) or adequate energy supply (green zone). Illustration by Annika Röhl. Cell Metabolism 2017 25, 57-71DOI: (10.1016/j.cmet.2016.09.017) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 ROS Production and Defense Systems in Mitochondria Superoxide (O2∗−) is produced at low levels from complex I and III during cellular respiration. O2∗− is quickly converted to hydrogen peroxide (H2O2) via superoxide dismutase 1 or 2 (SOD1 or SOD2). Neither O2∗− nor H2O2 efficiently reacts with DNA, but H2O2 can be converted to highly reactive hydroxyl radical (OH∗) through Fenton chemistry. The reactivity of OH∗ is only limited by diffusion, and it can react with any biomolecule. The formation of OH∗ can be limited by converting H2O2 to water via mitochondrial antioxidants such as gluthatione peroxidase 1 (GPX1) or by thioredoxin-dependent peroxiredoxin 3 (PRDX3). H2O2 can also function as a signaling molecule by reversibly oxidizing thiol groups, thus regulating the function of these proteins. H2O2 can diffuse out of mitochondria and also affect extracellular and cytosolic redox signaling. Some lesions that occur on mtDNA can be repaired via mitochondrial base excision repair (BER). In addition, mtDNA is not naked but packaged into mitochondrial nucleoids by transcription factor A (TFAM). Illustration by Annika Röhl. Cell Metabolism 2017 25, 57-71DOI: (10.1016/j.cmet.2016.09.017) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Recommended Breeding Scheme for the mtDNA Mutator Mouse Wild-type progeny of a heterozygous mtDNA mutator mouse will inherit, on average, two unique mutations per mtDNA and should therefore not be used as controls. Instead, a separate wild-type lineage should be used as wild-type controls. Mutation estimations from Ross et al. (2013). Cell Metabolism 2017 25, 57-71DOI: (10.1016/j.cmet.2016.09.017) Copyright © 2017 Elsevier Inc. Terms and Conditions