title: Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis.
abstract: The mechanisms of mitochondrial alterations in aged post-mitotic cells, including formation of so-called 'giant' mitochondria, are poorly understood. To test whether these large mitochondria might appear due to imperfect autophagic mitochondrial turnover, we inhibited autophagocytosis in cultured neonatal rat cardiac myocytes with 3-methyladenine. This resulted in abnormal accumulation of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, which is associated with slow accumulation of predominantly large defective mitochondria, pharmacological inhibition of autophagy caused only moderate accumulation of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, probably reflecting their normally more rapid turnover. Furthermore, the 3-methyladenine-induced accumulation of large mitochondria was irreversible, while small mitochondria gradually decreased in number after withdrawal of the drug. We, therefore, tentatively conclude that large mitochondria selectively accumulate in aging post-mitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Nevertheless, enlarged mitochondria retained 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 post-mitotic cells.
authors.affiliation: Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden. alex.terman@inr.liu.se
authors.forename: Alexei
authors.initials: A
authors.lastname: Terman
authors.forename: Helge
authors.initials: H
authors.lastname: Dalen
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D002470:Cell Survival; D016922:Cellular Senescence; D045304:Cytochromes c / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000096:biosynthesis*; D003576:Electron Transport Complex IV / Q000378:metabolism; D007150:Immunohistochemistry; D008247:Lysosomes; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure*; D018384:Oxidative Stress; D051381:Rats
chemical_list: D004272:DNA, Mitochondrial; C025946:3-methyladenine; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D000225:Adenine