Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover

Abstract

Bnip3 is a mitochondrial BH3-only protein that contributes to cell death through activation of the mitochondrial pathway of apoptosis. Bnip3 is also known to induce autophagy but the functional role of autophagy is unclear. In this study, we investigated the relationship between mitochondrial dysfunction and upregulation of autophagy in response to Bnip3 in cells lacking Bax and Bak. We found that Bnip3 induced mitochondrial autophagy in the absence of mitochondrial membrane permeabilization and Bax/Bak. Also, co-immunoprecipitation experiments showed that Bnip3 interacted with the autophagy protein LC3. Although Bax/Bak deficient cells were resistant to Bnip3-mediated cell death, inhibition of mitochondrial autophagy induced necrotic cell death. When investigating why these mitochondria had to be removed by autophagy, we discovered that Bnip3 reduced both nuclear and mitochondria-encoded proteins involved in oxidative phosphorylation. Interestingly, Bnip3 had no effect on other mitochondrial proteins such as Tom20 and MnSOD, or actin and tubulin in the cytosol. Bnip3 did not appear to reduce transcription or translation of these proteins. However, we found that Bnip3 caused an increase in mitochondrial protease activity, suggesting that Bnip3 might promote degradation of proteins in the mitochondria. Thus, Bnip3-mediated impairment of mitochondrial respiration induces mitochondrial turnover by activating mitochondrial autophagy.

Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS-mediated cardiomyocyte hypertrophy

“…Moreover, loss of EndoG, another mitochondrial endonuclease with high sequence similarity to EXOG (2), has recently been shown to induce cardiac hypertrophy (15). Although EndoG was originally believed to be a main regulator of caspase-independent regulation of DNA fragmentation and apoptosis (1,17), these new results suggest additional functions of this enzyme. Based on the current EXOG knowledge, and in analogy to EndoG, we hypothesized that EXOG would have additional functions in (cardio)myocytes.…”

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

“…Briefly, HIF1a can unbalance the ratio between pyruvate dehydrogenase and lactate dehydrogenase in favour of the latter (Semenza et al, 1996;Kim et al, 2006;Papandreou et al, 2006). Recently, the HIF1a target BNIP3 (Guo et al, 2001) was shown to mediate a similar global RC inhibition (Rikka et al, 2011). Besides these general RC inhibition mechanisms, it was demonstrated that HIF1a can also reduce RCC IV activity through the induction of microRNA-210 (Chen et al, 2010).…”

Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

“…During mitophagy, dysfunctional mitochondria are first segregated from the healthy network by fission and are then tagged for elimination (14, 37). Mitochondrial targeting can occur via mitophagy-specific receptors such as Bcl-2/adenovirus E1B 19-kDa interacting protein 3-like (Nix/Bnip3) (14,26,30) or by ubiquitination of mitochondrial outer membrane proteins by E3 ligases such as Parkin and Mul1 (4,21,25). Tagged mitochondria are then recognized by, and engulfed into, doublemembrane vesicles termed autophagosomes.…”