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Review
. 2013 Mar;123(3):951-7.
doi: 10.1172/JCI64125. Epub 2013 Mar 1.

The role of mitochondria in aging

Ana Bratic  1 , Nils-Göran Larsson
Affiliations
Review

V体育2025版 - The role of mitochondria in aging

Ana Bratic et al. J Clin Invest. 2013 Mar.

Abstract

Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging VSports手机版. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process. .

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Figure 1
Figure 1. Schematic model of the oxidative phosphorylation system and the production of ROS.
(A) ATP is generated by oxidative phosphorylation conducted by the four RC complexes (CI–CIV) and ATP synthase (CV) located in the inner mitochondrial membrane. Energy released by the electron transfer from NADH and FADH2 to O2 is used to pump protons (H+) via CI, CIII, and CIV. The proton gradient across the inner mitochondrial membrane drives ATP production via ATP synthase. The proton gradient can be dissipated by re-entry of protons to the mitochondrial matrix through uncoupling proteins (UCPs), which leads to uncoupling of respiration and ATP synthesis. (B) ROS are formed as a byproduct of oxidative phosphorylation. Superoxide is an abundant ROS in the cell and is generated by CI and CIII. Cells protect themselves from oxidative damage by expressing a variety of antioxidant enzymes that convert ROS into less harmful byproducts. Superoxide anion is converted to hydrogen peroxide by manganese SOD. Hydrogen peroxide is then converted to water by glutathione peroxidase, the most abundant peroxidase in the cytosol and mitochondria. Even though hydrogen peroxide is not substantially harmful for the cell, it can be converted to the highly reactive hydroxyl radical (OH•) in the presence of transition metals via the Fenton reaction. CytC, cytochrome C; CoQ, coenzyme Q10.
Figure 2
Figure 2. Model for mtDNA mutations in the stem cell hypothesis of aging.
Data from the mtDNA mutator mice suggest that increased mtDNA mutations that arise during development may, by affecting mitochondrial bioenergetic capacity, ROS production, or redox status of the cell, contribute to deregulated stem cell homeostasis and premature aging phenotypes. OXPHOS, oxidative phosphorylation.
Figure 3
Figure 3. Model for the effects of impaired IIS and CR on mitochondrial function and aging.
Mitochondrial metabolism plays an important role in mediating longevity promoted by nutrient-sensing pathways like the IIS, the TOR pathway, and CR. Impaired IIS leads to reduced availability of intracellular glucose and consequently to an elevated cellular AMP/ATP ratio that activates AMPK. In its turn, AMPK activates PGC-1α and increases mitochondrial metabolism and respiration rate, which consequently results in transient ROS production. The transient increase in ROS levels activates the expression of scavenging enzymes, e.g., SOD and catalase, resulting in decreased ROS levels, increased stress resistance, and extended life span. Furthermore, current findings suggest that the beneficial effect of CR on longevity is at least partly mediated by improved mitochondrial function mediated through activation of SIRT1 and PGC-1α. The activity of PGC-1α is tightly controlled via glycogen synthase kinase-3β (GSK3β), which acts via phosphorylation to prime PGC-1α for ubiquitinylation and degradation.
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