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Non-Hodgkin Lymphoma
Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):495-512
Aloke Sarkar,1 Christine M. Stellrecht,1,2 Hima V. Vangapandu,1 Mary Ayres,1 Benny A. Kaipparettu,3 Jun Hyoung Park,3 Kumudha Balakrishnan,1,4 Jared K. Burks,5 Tej K. Pandita,6 Walter N. Hittelman,1 Sattva S. Neelapu4 and Varsha Gandhi1,2,5
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center; 2The University of Texas Graduate School of Biomedical Sciences at Houston; 3Department of Molecular and Human Genetics, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine; 4Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center; 5Department of Leukemia, The University of Texas MD Anderson Cancer Center and 6Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX, USA
ABSTRACT
Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity, is frequently altered in human can- cers 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 resist- ant 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 mito- chondrial 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 lym- phomas without detectable ATM, Parkin, Pink1, and Parkin-UbSer65 phos- phorylation 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.
Introduction
Mitochondria are indispensable for generating the solitary cellular energy curren- cy, namely ATP, via oxidative phosphorylation and yet they exert damaging func- tions in altered pathophysiological scenarios including cancer.1-5 Reactive oxygen species (ROS) emanating from mitochondria can cause inevitable damage to these organelles’ own histone-devoid circular DNA with minimum proof-reading capac- ity encoding 37 genes - the prerequisite of the mitochondrial DNA (mtDNA) elec- tron transport chain. Widespread metabolic reprogramming, excessive generation
Correspondence:
VARSHA GANDHI
vgandhi@mdanderson.org
Received: August 9, 2019. Accepted: January 31, 2020. Pre-published: February 6, 2020.
https://doi.org/10.3324/haematol.2019.234385
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