p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3

Abstract

Abstract-Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death.Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial ∆Ψ m . This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53-indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3 −/− mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated.

Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling

“…Moreover, Bnip3 can promote autophagy/mitophagy in certain cells; however, this property of Bnip3 is obscure and likely occurs in a cell-and context-specific manner, given that we and others have found that Bnip3 can promote maladaptive autophagy, resulting in cell death (10,12,13).…”

“…Postnatal rat cardiac myocytes were isolated from 1-to 2-d-old Sprague-Dawley rats and subjected to primary culture as described previously. Cells were treated with DOX (5 or 10 μM; Pfizer) for 18 h. Cells were infected with adenoviruses encoding Bnip3 shRNA or a carboxyl terminal domain mutant of Bnip3 defective for mitochondrial targeting, designated Bnip3ΔTM, as reported previously (10,15,16).…”

“…A total of 3,000 cells for each condition were analyzed. Cardiac cell lysate and RNA from hearts were processed for Western blot and quantitative PCR (qPCR) analyses, as reported previously (10).…”

“…Indeed, Bnip3 gene activation can trigger mitochondrial perturbations consistent with mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential (ΔΨm), and cell death with features of necrosis (9,10). Notably, genetic interventions that antagonize the expression or integration of Bnip3 into mitochondrial…”

miR-210 Protects Renal Cell Against Hypoxia-induced Apoptosis by Targeting HIF-1 Alpha

“…We observed that in late hypoxia, though HIF-1α began to decline, the apoptosis-inducing factor BNIP3, a target gene of HIF-1α, also known as the target gene of miR-210 (49), was strengthened. This might be because p53 (50) activation induced a BNIP3 increase in late hypoxia. Except that miR-210 could suppress local hypoxia group.…”