Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma

• Published in: Haematologica (Roma) 2021-02, Vol.106 (2), p.495-512
• Main Authors: Sarkar, Aloke, Stellrecht, Christine M, Vangapandu, Hima V, Ayres, Mary, Kaipparettu, Benny A, Park, Jun Hyoung, Balakrishnan, Kumudha, Burks, Jared K, Pandita, Tej K, Hittelman, Walter N, Neelapu, Sattva S, Gandhi, Varsha
• Format: Article
• Language: English
• Subjects: Adult; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; HeLa Cells; Humans; Lymphoma, Mantle-Cell - genetics; Mice; Mitophagy - genetics; Phosphorylation; Protein Kinases - genetics; Protein Kinases - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2019.234385

Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity,is frequently altered in human cancers including mantle cell lymphoma (MCL). Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy, in both murine thymocytes and in A-T cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in MCL and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 MCL cells possess single copy and 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 mROS. 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 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 MCL, A-T 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-Ub ser65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of ATM's role in mitophagy in MCL and other B-cell lymphomas.