Fight against death: the role of autophagy in mitochondrial turnover in haematopoietic cells in vivo
Lead Research Organisation:
University of Oxford
Department Name: Clinical Medicine
Abstract
In this project we will investigate the role of a cellular process called autophagy in the development and maintenance of the immune system. Most of the large structures of the cell such as the energy-producing mitochondria are continuously being engulfed and degraded by a process known as autophagy (self-eating). Insufficient autophagy may allow damaged structures and molecules to build up within the cell, and contribute to neurodegeneration and ageing. Autophagy is also used by the cell to adapt to new circumstances: if we fast or starve, our cells chew up much of their contents by autophagy to mobilize resources for the rest of the body. We have shown that failure to undergo autophagy in red blood cells causes cell death and as consequence anaemia in the whole animal. Similarly we have preliminary data showing that absence of autophagy in immune cells (leukocytes) causes cell death resulting in very low numbers of leukocytes. We are proposing to investigate why autophagy is needed for the survival of leukocytes and elucidate how cells die in the absence of autophagy. To carry oxygen to every part of the body within tiny capillaries, red blood cells (erythrocytes) need to reduce their size. They do this towards the end of their development by losing most of their proteins and organelles including nucleus and mitochondria. A consequence of this process is the loss of their major source of energy, which condemns them to die within a short period of time. However, over the course of their short lifespan (approximately 120 days in man and 30 days in mice). They have accumulated haemoglobin and can continuously transport large amounts of oxygen. Whereas it was known for some time that the nucleus is expelled, it is unclear how red blood cells lose their organelles. Early electron micrographs from the 1960s show that erythrocytes contain mitochondria within double-membraned vesicles called autophagosomes. We have generated mice in which blood cells (both red and white cells) are knocked out for autophagy. These mice die of anaemia as their red blood cells die early due to the accumulation of damaged mitochondria which cannot be eliminated though autophagy. Even though leukocytes do not have such a strict developmental requirement to remove their mitochondria, we hypothesize that general mitochondrial turnover is regulated through autophagy in leukocytes. On top of being the energy factory of the cell, mitochondria play a central role in pronouncing the death sentence of the cell. This is probably no coincidence since the mitochondria are the main target for many noxious stimuli, such as toxins, free radicals, excessive calcium and lack of oxygen. The mitochondria are damaged by these fatal stimuli. Damaged mitochondria initiate the process of cell death. In fact we observe cell death in all different types of leukocytes obtained from autophagy deficient mice analysed so far. We will now investigate whether cell death is caused by damaged mitochondria in leukocytes, and whether other organelles are accumulating such as ribosomes, ER and Golgi. Excessive levels of autophagy can lead to cell death, however our results indicate it plays a role as a cell survival mechanism. We will therefore elucidate in molecular detail how leukocytes die in the absence of autophagy. Very little is known about the role autophagy in leukocytes, in particular in vivo. The results of this study will add important information to the understanding of mitochondrial turnover and will benefit the scientific community interested in these fundamental cellular processes. It will give an insight into the senescence of cells and the link between cell death and autophagy. Extending our findings on red blood cells to leukocytes will help to generalize the observed phenomenon and make it more likely to establish it as a universal process in all cells.
Technical Summary
Autophagy is a catabolic process whereby cells sequester long-lived proteins and damaged organelles for their degradation. Recently the main molecular players in autophagy have been identified, including members of the Atg gene family, providing new tools to trace, quantify and manipulate autophagy. Mammalian red blood cells are enucleated and devoid of organelles. While it has been known for some time that the nucleus is expelled, the molecular mechanism responsible for the removal of organelles remained unclear. Our lab has recently demonstrated that mitochondrial autophagy (mitophagy) mediated by Atg7 is essential in the removal of mitochondria from developing erythroid cells. We show that the absence of autophagy in erythrocytes in vivo decreases their lifespan and causes cell death in vivo. Damaged mitochondria accumulate in Atg7-/- erythroid cells and mice lacking the autophagy gene Atg7 in the haematopoietic system (Haem-Atg7-/-) die of anaemia. It is known that most other cell types also undergo mitophagy to remove damaged mitochondria and failure to do can be pathogenic. Interestingly, we found that HaemAtg7-/- mice are severely leukopenic with only 20% of normal T cell levels, severely reduced B cell numbers, arrested macrophage and dendritic cell development. Indeed, in all leukocytes investigated so far, we found that the absence of autophagy leads to spontaneous cell death. Our hypothesis is therefore that autophagy is the major degradative pathway in mitochondrial turnover in leukocytes and that in its absence leukocytes accumulate damaged mitochondria and possibly other organelles, leading to leukocyte death. We are proposing to investigate organelle turnover in autophagy deficient leukocytes in vivo. We will address a major controversy in the field whether autophagy is an alternative form of cell death or necessary for survival. Moreover we will elucidate the apoptotic pathways of programmed cell death in the absence of autophagy.
People |
ORCID iD |
Anna Simon (Principal Investigator) |
Publications
Rasmussen SB
(2011)
Activation of autophagy by a-herpesviruses in myeloid cells is mediated by cytoplasmic viral DNA through a mechanism dependent on stimulator of IFN genes.
in Journal of immunology (Baltimore, Md. : 1950)
Simon AK
(2013)
T. rex attacks the lysosome.
in Nature immunology
Wallace ZR
(2016)
Exposure to zidovudine adversely affects mitochondrial turnover in primary T cells.
in Antiviral research
Watson A
(2015)
Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia
in Cell Death Discovery
Watson AS
(2011)
Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia.
in Cell cycle (Georgetown, Tex.)
Description | Autophagy, a cellular major degradation pathway, is essential in the maintenance of hematopoietic stem cells, the formation of the memory T cell pool and to delay immune system senescence |
Exploitation Route | to improve regenerative medicine, to treat haematological malignancies, to improve vaccination in the elderly |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
URL | http://www.ndm.ox.ac.uk/principal-investigators/researcher/anna-katharina-katja-simon |
Description | Mostly within the scientific community - drug development is still ongoing |
First Year Of Impact | 2011 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | Member of Deutsche Forschungsgemeinschaft committee for SFB |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Andrew McMichael Fund - Postdoctoral Fellowship (Monika Mortensen) |
Amount | £103,000 (GBP) |
Organisation | University of Oxford |
Department | Weatherall Institute of Molecular Medicine (WIMM) |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2010 |
End | 01/2012 |
Description | Impact of autophagy and asymmetric cell division on HSCs differentiation |
Amount | £250,000 (GBP) |
Funding ID | EU project 893676 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start |
Description | Kidney Research UK - Mechanism of interstital nephritis, fibrosis and renal faliure due to Uromodulin mutations |
Amount | £235,920 (GBP) |
Funding ID | RP52/2012 |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2012 |
End | 01/2015 |
Description | Lady Tata Consumables funding |
Amount | £30,000 (GBP) |
Organisation | Lady Tata Memorial Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2012 |
End | 12/2014 |
Description | Project Grant - Developing induced pluripotent stem cells as a model to investigate tissue specific mitochondrial disease |
Amount | £251,826 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2012 |
End | 01/2015 |
Description | Wellcome Trust New investigator Award |
Amount | £962,500 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2014 |
End | 08/2019 |
Description | Wellcome Trust Project Grant - Developing treatments for mitochondrial DNA diseases |
Amount | £251,826 (GBP) |
Funding ID | 0948685/Z/10/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2011 |
End | 04/2014 |
Description | Wellcome Trust Project Grant - Role of autophagy in anaemia and MDS |
Amount | £185,485 (GBP) |
Funding ID | 088098 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2010 |
End | 01/2013 |
Description | NIH: Improving T Cell Response to Hepatitis C Virus via Modulation of Autophagy |
Organisation | National Institutes of Health (NIH) |
Department | Center for Human Immunology, Autoimmunity and Inflammation |
Country | United States |
Sector | Public |
PI Contribution | We are doing the experiments, providing the tools and ideas. |
Collaborator Contribution | The consortium contributes technological platforms, discussion and samples. |
Impact | Not yet. |
Start Year | 2015 |
Description | NIHR salary: improving human T cell responses via autophagy |
Organisation | Oxford University Hospitals NHS Foundation Trust |
Department | NIHR Oxford Biomedical Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are providing the tools, knowledge and data |
Collaborator Contribution | Provision of salary for junior research fellow, human samples and expertise |
Impact | none yet |
Start Year | 2017 |
Title | Polyamines compounds and uses thereof |
Description | Using Spermidine to boost the immune system in the elderly, to improve the efficacy of vaccinations |
IP Reference | MPS/EOR/P129835GB01 |
Protection | Patent application published |
Year Protection Granted | 2014 |
Licensed | No |
Impact | none as yet |
Description | Lab experience for Baccalaureat class |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A European school arranged to have an annual visit to my lab for their first year baccalaureate students, giving them supervised hands on experience of working in a lab Further enquiries about how to get in to a career in science |
Year(s) Of Engagement Activity | 2007,2008,2009,2010,2011,2012 |
Description | Lecture - West Oxford Academy |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Talk given to the general about my research, which was followed by a question and answer session. Enquiries from some of the younger members of the audience in how to get into research |
Year(s) Of Engagement Activity | 2008,2011 |
Description | Press release for elife paper: Interview with BBC Radio Oxford |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview given. further enquiries from the media about the paper and my research |
Year(s) Of Engagement Activity | 2014 |