New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart

Abstract

The heart is highly sensitive to the aging process. In the elderly, the heart tends to become hypertrophic and fibrotic. Stiffness increases with ensuing systolic and diastolic dysfunction. Aging also affects the cardiac response to stress. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. The accumulation of dysfunctional and abnormal mitochondria is an important pathophysiological feature of the aging process, which is associated with excessive production of reactive oxygen species. Mitochondrial fusion and fission and mitochondrial autophagy are crucial mechanisms for maintaining mitochondrial function and preserving energy production. In particular, mitochondrial fission allows for selective segregation of damaged mitochondria, which are afterward eliminated by autophagy. Unfortunately, recent evidence indicates that mitochondrial dynamics and autophagy are progressively impaired over time, contributing to the aging process. This suggests that restoration of these mechanisms could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of the close relationship between mitochondrial dynamics, mitophagy, oxidative stress, and aging, with a particular focus on the heart.

Figure 1

Autophagy machinery. Schema representing the four stages of the autophagic process.

Figure 2

Mitochondrial dynamics. Schema explaining the main functions of mitochondrial fusion and fission.

Figure 3

Mechanisms of mitophagy induction. Schema representing the main mechanisms of mitophagy induction. PINK1 accumulates in damaged mitochondria and phosphorylates mitofusin-2. Phosphorylated mitofusin-2 recruits parkin, which ubiquitinates several mitochondrial targets. Mitochondrial ubiquitination by parkin promotes mitophagy.

Figure 4

The importance of autophagy in the aged heart. Aging inhibits autophagy and affects mitochondrial dynamics. Autophagy inhibition is associated with accumulation of damaged mitochondria and oxidative stress, which favor the development of cardiovascular diseases.