Functions of BCL-XL at the Interface between Cell Death and Metabolism

The BCL-2 homolog BCL-XL, one of the two protein products of BCL2L1, has originally been characterized for its prominent prosurvival functions. Similar to BCL-2, BCL-XL binds to its multidomain proapoptotic counterparts BAX and BAK, hence preventing the formation of lethal pores in the mitochondrial outer membrane, as well as to multiple BH3-only proteins, thus interrupting apical proapoptotic signals. In addition, BCL-XL has been suggested to exert cytoprotective functions by sequestering a cytosolic pool of the pro-apoptotic transcription factor p53 and by binding to the voltage-dependent anion channel 1 (VDAC1), thereby inhibiting the so-called mitochondrial permeability transition (MPT). Thus, BCL-XL appears to play a prominent role in the regulation of multiple distinct types of cell death, including apoptosis and regulated necrosis. More recently, great attention has been given to the cell death-unrelated functions of BCL-2-like proteins. In particular, BCL-XL has been shown to modulate a number of pathophysiological processes, including—but not limited to—mitochondrial ATP synthesis, protein acetylation, autophagy and mitosis. In this short review article, we will discuss the functions of BCL-XL at the interface between cell death and metabolism. 1. Introduction According to current models, cell death most often proceeds via either of two relatively independent subroutines, apoptosis, and necrosis [1, 2]. For a long time, apoptotic and necrotic instances of cell death have exclusively been identified based on morphological criteria [2]. In addition, while apoptosis was believed to constitute the sole regulated (i.e., genetically encoded, and hence susceptible to pharmacological modulation) modality of cell death, necrosis was viewed as a purely accidental process [3]. Recently, a functional classification of cell death mechanisms, based on measurable biochemical features, has been proposed [1], and the concept of regulated necrosis has gained large consensus [4]. In this scenario, the true relevance of additional processes that were previously catalogued as bona fide cell death subroutines is being reevaluated. In particular, while macroautophagy (hereafter referred to as autophagy) turned out to constitute a prominent homeostatic and cytoprotective mechanism [5, 6], autophagic cell death (a lethal subroutine that is mediated, rather than merely accompanied, by autophagy) has been shown to occur in a limited number of, mostly developmental, scenarios [1, 7]. Along similar lines, mitotic catastrophe, a signaling cascade elicited in