TY - JOUR
T1 - Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma
AU - Sarkar, Aloke
AU - Stellrecht, Christine
AU - Vangapandu, Hima V.
AU - Ayres, Mary
AU - Kaipparettu, Benny A.
AU - Park, Jun Hyoung
AU - Balakrishnan, Kumudha
AU - Burks, Jared K.
AU - Pandita, Tej K.
AU - Hittelman, Walter N
AU - Neelapu, Sattva S.
AU - Gandhi, Varsha
N1 - Funding Information:
We thank Dr. Sankar Mitra, Methodist Research Institute, Houston, TX, USA for crtically reviewing the manuscript. We also thank Dr. Richard Youle, NIH for providing us with the YFP-Parkin plasmid, Dr. Noriyuki Matsuda, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan for providing us with the GFP-Parkin construct and Rakesh Sharma, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, USA for processing and distributing the primary B-cell lymphomas. This work was supported by a CLL Global Research Foundation Alliance grant. A part of this work was performed in the Flow Cytometry and Cellular Imaging Facility, supported in part by the NIH through MD Anderson’s Cancer Center Support grant CA016672.
Funding Information:
We thank Dr. Sankar Mitra, Methodist Research Institute, Houston, TX, USA for crtically reviewing the manuscript. We also thank Dr. Richard Youle, NIH for providing us with the YFP-Parkin plasmid, Dr. Noriyuki Matsuda, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan for providing us with the GFP-Parkin construct and Rakesh Sharma, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, USA for processing and distributing the primary B-cell lymphomas. This work was supported by a CLL Global Research Foundation Alliance grant. A part of this work was performed in the Flow Cytometry and Cellular Imaging Facility, supported in part by the NIH through MD Anderson's Cancer Center Support grant CA016672.
Publisher Copyright:
© 2021 Ferrata Storti Foundation
PY - 2021/2
Y1 - 2021/2
N2 - Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, is frequently altered in human cancers including mantle cell lymphoma. Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy in both murine thymocytes and in ataxia-telangiectasia cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in mantle cell lymphoma and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 mantle cell lymphoma cells possess single copy kinase-dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATM-proficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mitochondrial reactive oxygen species. ATM interacts with the E3 ubiquitin ligase Parkin in a kinase-independent manner. Knockdown of ATM in HeLa cells resulted in proteasomal degradation of GFP-Parkin which was rescued by the proteasome inhibitor, MG132, suggesting that the ATM-Parkin interaction is important for Parkin stability. Neither loss of ATM kinase activity in primary B-cell lymphomas nor inhibition of ATM kinase in mantle cell lymphoma, ataxia-telangiectasia and HeLa cell lines mitigated FCCP- or CCCP-induced mitophagy suggesting that ATM kinase activity is dispensable for mitophagy. Malignant B-cell lymphomas without detectable ATM, Parkin, Pink1, and Parkin-UbSer65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of the role of ATM in mitophagy in mantle cell lymphoma and other B-cell lymphomas.
AB - Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, is frequently altered in human cancers including mantle cell lymphoma. Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy in both murine thymocytes and in ataxia-telangiectasia cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in mantle cell lymphoma and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 mantle cell lymphoma cells possess single copy kinase-dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATM-proficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mitochondrial reactive oxygen species. ATM interacts with the E3 ubiquitin ligase Parkin in a kinase-independent manner. Knockdown of ATM in HeLa cells resulted in proteasomal degradation of GFP-Parkin which was rescued by the proteasome inhibitor, MG132, suggesting that the ATM-Parkin interaction is important for Parkin stability. Neither loss of ATM kinase activity in primary B-cell lymphomas nor inhibition of ATM kinase in mantle cell lymphoma, ataxia-telangiectasia and HeLa cell lines mitigated FCCP- or CCCP-induced mitophagy suggesting that ATM kinase activity is dispensable for mitophagy. Malignant B-cell lymphomas without detectable ATM, Parkin, Pink1, and Parkin-UbSer65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of the role of ATM in mitophagy in mantle cell lymphoma and other B-cell lymphomas.
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U2 - 10.3324/haematol.2019.234385
DO - 10.3324/haematol.2019.234385
M3 - Article
C2 - 32029507
AN - SCOPUS:85100649853
SN - 0390-6078
VL - 106
SP - 495
EP - 512
JO - Haematologica
JF - Haematologica
IS - 2
ER -