Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation.

Abstract:

:Mitochondrial clearance is a well recognized but poorly understood biologic process, and reticulocytes, which undergo programmed mitochondrial clearance, provide a useful model to study this phenomenon. At the ultrastructural level, mitochondrial clearance resembles an autophagy-related process; however, the role of autophagy in mitochondrial clearance has not been established. Here we provide genetic evidence that autophagy pathways, initially identified in yeast, are involved in mitochondrial clearance from reticulocytes. Atg7 is an autophagy protein and an E1-like enzyme, which is required for the activity of dual ubiquitin-like conjugation pathways. Atg7 is required for the conjugation of Atg12 to Atg5, and Atg8 to phosphatidylethanolamine (PE), and is essential for autophagosome formation. In the absence of Atg7, mitochondrial clearance from reticulocytes is diminished but not completely blocked. Mammalian homologs of Atg8 are unmodified in Atg7(-/-) erythroid cells, indicating that canonical autophagy pathways are inactive. Thus, mitochondrial clearance is regulated by both autophagy-dependent and -independent mechanisms. In addition, mitochondria, which depolarize in wild-type cells before elimination, remain polarized in Atg7(-/-) reticulocytes in culture. This suggests that mitochondrial depolarization is a consequence rather than a cause of autophagosome formation in reticulocytes.

journal_name

Blood

journal_title

Blood

authors

Zhang J,Randall MS,Loyd MR,Dorsey FC,Kundu M,Cleveland JL,Ney PA

doi

10.1182/blood-2008-04-151639

subject

Has Abstract

pub_date

2009-07-02 00:00:00

pages

157-64

issue

1

eissn

0006-4971

issn

1528-0020

pii

blood-2008-04-151639

journal_volume

114

pub_type

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