The role of mitochondrial proteases in leukemic cells and leukemic stem cells

Abstract

Abstract The biological function of most mitochondrial proteases has not been well characterized. Moreover, most of the available information on the normal function of these proteases has been derived from studies in model organisms. Recently, the mitochondrial proteases caseinolytic protease P (CLPP) and neurolysin (NLN) have been identified as therapeutic targets in acute myeloid leukemia (AML). Both proteases are overexpressed in approximately 40% of AML patients. Mechanistically, CLPP and NLN maintain the integrity of the mitochondrial respiratory chain: CLPP cleaves defective respiratory chain proteins, while NLN promotes the formation of respiratory chain supercomplexes. In this review, we highlight the functional consequences of inhibiting and activating mitochondrial proteases and discuss their potential as therapeutic targets in AML. Significance statement Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Despite recent advances and new therapies for this disease, the prognosis for most patients with AML remains poor. Understanding the biology of this disease is important for developing new therapies. Recently, AML cells and stem cells have been shown to have unique mitochondrial properties, which can be therapeutically targeted. One of these properties is an increased reliance on the mitochondrial matrix proteases, caseinolytic protease P and neurolysin. This perspective discusses the effects of genetically and chemically dysregulating mitochondrial proteases in AML. Moreover, this study considers the potential of targeting mitochondrial proteases as a novel therapeutic strategy.