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.

The role of lysosomes in iron metabolism and recycling

“…The lysosomal hydrolases are then activated when they release the MP receptors that are recirculated to the Golgi apparatus. Finally, the late endosomes mature to lysosomes that lack MP receptors, are rich in acid hydrolases, have a pH of 4-5, and contain material to be degraded (Terman et al, 2010).…”

“…acridine orange or other available lysotrackers, it was found that after heavy oxidative stress some lysosomes always remain intact, while even low oxidative stress results in the rupture of a small but obviously very sensitive population of lysosomes (Nilsson et al, 1997). The explanation for this phenomenon is probably that some lysosomes are actively engaged in degradation of iron-containg macromolecules, while resting lysosomes may contain little or none of this transition metal (Terman et al, 2010).…”

“…3). Dependent on the magnitude of lysosomal rupture, cell proliferation is stimulated or arrested by a minor or a somewhat more pronounced lysosomal destabilization, respectively, while apoptosis or necrosis have been found to follow moderate or major destabilization, respectively (Li et al, 2000, Terman et al, 2010. Consequently, the amelioration of LMP by chelating lysosomal redox-active iron in a non-redox-active form ought to reduce radiation sensitivity.…”

“…Iron is, however, also associated with harmful processes, many of which take place inside the lysosomal compartment where iron occurs in low mass redox-active form, creating Fenton-type reactions with hydrogen peroxide that may diffuse from the cytosol (vide infra). As a consequence, lysosomes may be destabilized or accumulate the age pigment lipofuscin with secondary depression of autophagic capacity , Terman et al, 2010.…”

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…This morphology has been demonstrated to increase metabolic demands and the risk of oxidative stress in A9 cells compared to other dopaminergic cell populations (128)(129)(130). Long axons require more energy to accommodate transport machinery to and from soma, while the low diameter impairs motility and further increases the metabolic demands (131,132). Further, lack of nodes of Ranvier elevates Na + /K + activity due to a less efficient action potential mechanism (133).…”