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

Yoshiyuki Ikeda,Giacomo Frati,Junichi Sadoshima,Massimo Volpe,Sebastiano Sciarretta,Speranza Rubattu,Narayani Nagarajan

doi:10.1155/2014/210934

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.

Highlights

Over the past few decades, the human life span has been extended and is expected to increase further in the few years with a supplementary prolongation of life expectancy
We recently found that Reactive oxygen species (ROS) can directly oxidize AMPK at cysteines 130 and 174 and inhibit its activity in cardiomyocytes [40]
We found that activation of AMPK [131] and glycogen synthase kinase (GSK)-3β [132] as well as inhibition of Ras homolog enriched in brain (Rheb) [133] contributes to autophagy activation through the inhibition of mTORC1

Summary

Introduction

Over the past few decades, the human life span has been extended and is expected to increase further in the few years with a supplementary prolongation of life expectancy. Oxidative damage of mtDNA contributes to impairment of the electron transport chain, to mitochondrial uncoupling, and, to bioenergetic dysfunction of mitochondria characterized by reduced ATP production and further accumulation of ROS [46, 47]. Overexpression of catalase in subcellular organelles other than mitochondria failed to extend life span in mice, and overexpression of different isoforms of superoxide dismutase and peroxidase enzymes was not associated with a significant extension of longevity [54, 55] These results suggest that accumulation of ROS, hydrogen peroxide, in mitochondria, but not in other organelles, contributes to the aging process in mammals. Damaged mitochondria undergo quality control through selective elimination by mitophagy [17]

Autophagy and Cardiac Aging

Mitochondrial Elimination by Autophagy

Perspectives