Knockdown of BNIP3L or SQSTM1 alters cellular response to mitochondria target drugs. Issue 5 (4th May 2019)

• Record Type: Journal Article
• Authors: Rodrigo, Rowena; Mendis, Nilmini; Ibrahim, Medhat; Ma, Christina; Kreinin, Elena; Roma, Alessia; Berg, Spencer; Blay, Jonathan; Spagnuolo, Paul A.
• Is Part Of: Autophagy. Volume 15:Issue 5(2019)
• Page Start: 900
• Page End: 907
• Publication Date: 2019-05-04
• Subjects: Acute myeloid leukemia -- autophagy -- BNIP3L -- chemosensitivity -- mitochondria -- SQSTM1; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2018.1558002
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: Macroautophagy/autophagy, a pathway by which cellular components are sequestered and degraded in response to homeostatic and cell stress-related signals, is required to preserve hematopoietic stem and progenitor cell function. Loss of chromosomal regions carrying autophagy genes and decreased autophagy gene expression are characteristic of acute myeloid leukemia (AML) cells. Deficiency of autophagy proteins is also linked to an altered AML metabolic profile; altered metabolism has recently emerged as a potential druggable target in AML. Here, we sought to understand the mitochondria-specific changes that occur in leukemia cells after knockdown of BNIP3L/Nix or SQSTM1/p62, which are two autophagy genes involved in mitochondrial clearance and are downregulated in primary AML cells. Mitochondrial function, as measured by changes in endogenous levels of reactive oxygen species (ROS) and mitochondrial membrane potential, was altered in leukemia cells deficient in these autophagy genes. Further, these AML cells were increasingly sensitive to mitochondria-targeting drugs while displaying little change in sensitivity to DNA-targeting agents. These findings suggest that BNIP3L or SQSTM1 may be useful prognostic markers to identify AML patients suitable for mitochondria-targeted therapies. Abbreviations: AML: acute myeloid leukemia; DHE: dihydroethidium; mtDNA: mitochondrial DNA; NAO: 10-N-nonyl acridine orange; PD: population doubling; R123: rhodamine 123; ROS: reactive oxygen species; TRC: transduced scramble controls