Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 2, Pages 832-837Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913170107
Keywords
Atg7; mitophagy; lymphopenia; cell death; reactive oxygen species
Categories
Funding
- National Institute for Health Research Biomedical Research Centre and the Association
- Medical Research Council
- Andrew McMichael Fund
- Biotechnology and Biological Sciences Research Council
- BBSRC [BB/G021422/1] Funding Source: UKRI
- MRC [G0500695, G0501068] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G021422/1] Funding Source: researchfish
- Medical Research Council [G0501068, G0500695] Funding Source: researchfish
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Timely elimination of damaged mitochondria is essential to protect cells from the potential harm of disordered mitochondrial metabolism and release of proapoptotic proteins. In mammalian red blood cells, the expulsion of the nucleus followed by the removal of other organelles, such as mitochondria, are necessary differentiation steps. Mitochondrial sequestration by autophagosomes, followed by delivery to the lysosomal compartment for degradation (mitophagy), is a major mechanism of mitochondrial turnover. Here we show that mice lacking the essential autophagy gene Atg7 in the hematopoietic system develop severe anemia. Atg7(-/-) erythrocytes accumulate damaged mitochondria with altered membrane potential leading to cell death. We find that mitochondrial loss is initiated in the bone marrow at the Ter119(+)/CD71(High) stage. Proteomic analysis of erythrocyte ghosts suggests that in the absence of autophagy other cellular degradation mechanisms are induced. Importantly, neither the removal of endoplasmic reticulum nor ribosomes is affected by the lack of Atg7. Atg7 deficiency also led to severe lymphopenia as a result of mitochondrial damage followed by apoptosis in mature T lymphocytes. Ex vivo short-lived hematopoietic cells such as monocytes and dendritic cells were not affected by the loss of Atg7. In summary, we show that the selective removal of mitochondria by autophagy, but not other organelles, during erythropoeisis is essential and that this is a necessary developmental step in erythroid cells.
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