Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of Aging

Abstract

It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. These cells are rarely or not at all replaced during life and can be as old as the whole organism. The inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged structures completely results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin, an intralysosomal indigestible material. In this review, we stress the importance of crosstalk between mitochondria and lysosomes in aging. The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced turnover of effective mitochondria. The latter not only are functionally deficient but also produce increased amounts of reactive oxygen species, prompting lipofuscinogenesis. Moreover, defective and enlarged mitochondria are poorly autophagocytosed and constitute a growing population of badly functioning organelles that do not fuse and exchange their contents with normal mitochondria. The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival. Antioxid. Redox Signal. 12, 503–535.

Introduction

ROS, Mitochondrial Damage, and Aging

• Biomolecular damage under normal conditions

• Imperfect turnover of damaged biologic structures

• Major targets of ROS attack: mitochondria and lysosomes

Mitochondrial Fusion, Fission, and Biogenesis

• The role of mitochondrial dynamics

• Mitochondrial fusion

• Mitochondrial fission

• Mitochondrial biogenesis

Mitochondrial Proteolytic Systems

Mitochondrial Turnover by Autophagy

• The main functions of the lysosomal compartment

• Autophagy

• Autophagic degradation of mitochondria (mitophagy)

Lipofuscin Formation and Its Influence on Autophagy

• Influence of labile iron and ROS on lipofuscin formation

• Consequences of the nondegradability of lipofuscin

• Disease-related accumulation of intralysosomal and extralysosomal waste

Imperfect Mitochondrial Turnover and Postmitotic Cellular Aging

• Age-related accumulation of defective mitochondria within postmitotic cells

• Age-related decline in autophagy and Lon protease activity accelerates mitochondrial damage

• Enlarged mitochondria are resistant to degradation and do not fuse with normal ones

• Mechanisms of the age-related accumulation of mitochondria with homoplasmic mtDNA mutations

• Decreased mitochondrial biogenesis in aged cells

Summary and Conclusions