Mitochondrial aging and age-related dysfunction of mitochondria

Abstract

Age-related changes in mitochondria are associated with decline in mitochondrial function. With advanced age, mitochondrial DNA volume, integrity and functionality decrease due to accumulation of mutations and oxidative damage induced by reactive oxygen species (ROS). In aged subjects, mitochondria are characterized by impaired function such as lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, significant increase in ROS generation, and diminished antioxidant defense. Mitochondrial biogenesis declines with age due to alterations in mitochondrial dynamics and inhibition of mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells. However, implementation of strategies such as caloric restriction and regular physical training may delay mitochondrial aging and attenuate the age-related phenotype in humans.

Figure 1

Different ultrastructural appearances of mitochondria in the aortic intima ((a)–(f)). (a) A typical appearance of a mitochondrion in a grossly normal aorta. (b) A mitochondrion with well-defined cristae and well-preserved surrounding membranes in a lipofibrous plaque. ((c)–(f)) Structural variants and destructive alterations of cristae of mitochondria in lipofibrous plaques. In ((c)–(f)), the formation of vacuole-like structures in zones of oedematous matrix of mitochondria is shown by arrows. ((a)–(f)) Electron microscopy scales = 200 nm (reprinted from Atherosclerosis; Sobenin et al. Changes of mitochondria in atherosclerosis: possible determinant in the pathogenesis of the disease 2013; 227 : 283–288 [38], with permission from Elsevier).

Figure 2

Mechanisms by which caloric restriction may improve mitochondrial function, delay mitochondrial aging, and expend longevity. Caloric restriction (CR) triggers several pathways that may lead to increased longevity via stimulation of mitochondrial function. The first mechanism includes the induction of sirtuin-1 (SIRT1), a protein deacetylase that in turn activates peroxisome proliferator-activated receptor-γ coactivator-α (PGC-1α). PGC-1α is a transcription factor involved in the activation of genes whose products are involved in mitochondrial biogenesis and respiration. CR also inhibits mammalian target of rapamycin (mTOR) signaling associated with an increase in the activity of eukaryotic translation initiation factor 4E binding protein (4E-BP) that stimulates the translation of genes encoding mitochondrial respiratory components. In C. elegans, CR activates the nuclear factor-erythroid 2-related factor-2 (NRF2) that regulates expression of several antioxidant genes and therefore may lengthen C. elegans lifespan through the reduction of oxidative stress and improving mitochondrial respiration.