Aging of cardiac myocytes and mitochondrial turnover





A. Terman, U.T. Brunk

Division of Pathology II, Faculty of Health Sciences, Linkoping University, SE-581 85 Linkoping, Sweden



Aging preferentially affects postmitotic cells, such as cardiac myocytes and neurons, and is associated with intralysosomal lipofuscin accumulation and with oxidant-induced mitochondrial damage. Autophagy provides for continuous recycling of old and damaged mitochondria, and this process is hampered by lipofuscin deposition. To test whether age-related mitochondrial changes, including the formation of so-called 'giant' mitochondria, might originate from imperfect mitochondrial turnover, we inhibited autophagy in cultured neonatal rat cardiac myocytes with 3-methyladenine (3MA). The result was an abnormal amassing of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, associated with a slow accumulation of predominantly large, structurally deteriorated and functionally deficient mitochondria, pharmacological inhibition of autophagy caused only a moderate increases in the numbers of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, reflecting their rapid turnover. The 3MA-induced moderate accumulation of large mitochondria was irreversible, while the number small mitochondria gradually decreased after withdrawal of the drug. We tentatively conclude that large mitochondria selectively accumulate with age in postmitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Despite this, the enlarged mitochondria retained their immunoreactivity for cytochrome c oxidase subunit 1, implying that mitochondrial genes remain active in defective mitochondria. Our findings suggest that imperfect autophagic recycling of these critical organelles may underlie the progressive mitochondrial damage which characterizes aging postmitotic cells and may lead to increased oxidative stress and apoptosis due to lysosomal rupture.




Key words: Aging, autophagy, cardiac myocytes, lysosomes, mitochondria







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