Cofactor Strap regulates oxidative phosphorylation and mitochondrial p53 activity through ATP synthase

Abstract

Metabolic reprogramming is a hallmark of cancer cells. Strap (stress-responsive activator of p300) is a novel TPR motif OB-fold protein that contributes to p53 transcriptional activation. We show here that, in addition to its established transcriptional role, Strap is localised at mitochondria where one of its key interaction partners is ATP synthase. Significantly, the interaction between Strap and ATP synthase downregulates mitochondrial ATP production. Under glucose-limiting conditions, cancer cells are sensitised by mitochondrial Strap to apoptosis, which is rescued by supplementing cells with an extracellular source of ATP. Furthermore, Strap augments the apoptotic effects of mitochondrial p53. These findings define Strap as a dual regulator of cellular reprogramming: first as a nuclear transcription cofactor and second in the direct regulation of mitochondrial respiration.

OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore

“…Mitochondrial p53 also increased oxygen consumption and decreased ROS levels, suggesting that it may play a role in mitochondrial physiology (Bergeaud et al ., ). Finally, the newly characterized protein stress responsive activator p300 (Strap), which is known to increase p53 transcripts, has been shown to interact with β subunit of F‐ATP synthase decreasing ATP production (Maniam et al, ). As cancer cells are sensitized to apoptosis by mitochondrial Strap under glucose‐limiting conditions, the interaction of Strap with F‐ATP synthase might contribute to the pro‐apoptotic effects of p53.…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…All the three members promote mitochondrial respiration thought regulation of different metabolic enzymes, including the glutaminase 2 (Gls2) (Adamovich et al, 2014;Amelio et al, 2014b;Bellomaria et al, 2010Bellomaria et al, , 2012Giacobbe et al, 2013;He et al, 2013;Hu et al, 2010;Sharif et al, 2015;Simon et al, 2014;Velletri et al, 2013;Viticchie et al, 2015). Gls2 regulates glutamine utilization, supplying anaplerotic flux of substrates resulting in promotion of mitochondrial activity and ATP synthesis (Amelio et al, 2014a;Maniam et al, 2015). In addition p53 and TAp73 control expression of key components involved in oxidative phosphorylation, such as the cytochrome c oxidase 2 (SCO2) (Matoba et al, 2006) and the Cytochrome C Oxidase Subunit IV Isoform 1A COX4i1A (Rufini et al, 2012), respectively.…”

p53 is required for brain growth but is dispensable for resistance to nutrient restriction during Drosophila larval development

“…It is plausible that p53 binds to different genomic sites in larvae and adult flies, or the presence of cofactors or binding partners may regulate p53 activity. Several reports have shown the regulation of vertebrate p53 function by different cofactors [ 51 – 55 ], however, it is unknown which cofactor may modulate p53 function in Drosophila .…”