LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

Abstract

p53 is a major cellular tumor suppressor that in addition to its nuclear, transcription-dependent activity is also known to function extranuclearly. Cellular stressors such as reactive oxygen species can promote translocation of p53 into mitochondria where it acts to protect mitochondrial genome or trigger cell death via transcription-independent manner. Here we report that the mammalian homologue of yeast mitochondrial Afg1 ATPase (LACE1) promotes translocation of p53 into mitochondria. We further show that LACE1 exhibits significant pro-apoptotic activity, which is dependent on p53, and that the protein is required for normal mitochondrial respiratory function. LACE1 physically interacts with p53 and is necessary for mitomycin c-induced translocation of p53 into mitochondria. Conversely, increased expression of LACE1 partitions p53 to mitochondria, causes reduction in nuclear p53 content and induces apoptosis. Thus, LACE1 mediates mitochondrial translocation of p53 and its transcription-independent apoptosis.

The AAA ATPase Afg1 preserves mitochondrial fidelity and cellular health by maintaining mitochondrial matrix proteostasis

“…Second, the ability of high-copy Afg1 to compensate for the loss of mitochondrial Hsp70 chaperone or otherwise rescue its function strongly suggests that Afg1 can act more broadly and engage with different types of unfolded mitochondrial proteins. Of note, this result could potentially explain the observation by Cesnekova et al suggesting a mammalian Afg1 ortholog has a role in mediating the mitochondrial import of p53 under stress (Cesenkova et al, 2016b). Finally, we show that Afg1 helps to alleviate deleterious effects caused by expression of the misfolding-prone mouse DHFR in the matrix.…”

“…In yeast and mammalian mitochondria, this conserved AAA ATPase resides in the matrix and exists as a large, presumably homo-oligomeric (Babu et al, 2012), complex tightly associated with the IMM (Khalimonchuk et al, 2007;Cesenkova et al, 2016a). Previous studies have implicated Afg1 in mitochondrial protein homeostasis by showing that Afg1 aids in the degradation of cytochrome c oxidase (CcO) subunits in yeast (Khalimonchuk et al, 2007) and mammalian cells (Cesenkova et al, 2016a), and promotes stressinduced translocation of the tumor protein p53 into mammalian mitochondria (Cesenkova et al, 2016b). However, the significance of these observations and the physiological role of this protein remain far from clear.…”

SirT3 and p53 Deacetylation in Aging and Cancer

“…Stress stimuli activate p53 through post‐translational modifications that increase its stability and activity. Activated p53 binds to a specific DNA sequence or response elements (RE's), and regulates the transcriptions of a large number of down‐stream genes including cell cycle arrest, apoptosis, cell growth, aerobic glycolysis suppression, oxidative phosphorylation facilitation, and protein translation (Hasty and Christy, ; Cesnekova et al, ). p53 regulated genes for cell cycle arrest included p21, cdc25c, GADD45, 14‐3‐3s, and RPRM.…”

ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype

“…For ZapE, a spectrum of seemingly unrelated functions ranging from apoptosis to cell division has been proposed [5][6][7]9]. Curiously, it was not yet addressed how a single protein may perform such a plethora of functions.…”

“…Furthermore, both organisms lack the FtsZ division system [3]. ZapE was shown to mediate the translocation of p53 and subsequent apoptosis in humans [7]. It is also noteworthy that ZapE was highly affected in the proteomic survey of the Oxa1 depletome in humans [8].…”