Acetyl-Coenzyme A acyltransferase 2 attenuates the apoptotic effects of BNIP3 in two human cell lines

Cao, Wei; Liu, Nansong; Tang, Shuai; Bao, Lei; Shen, Li; Yuan, Hao; Zhao, Xin; Lü, Hong

doi:10.1016/j.bbagen.2008.02.007

Cited by 53 publications

(41 citation statements)

References 24 publications

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“…Many results point to an important role of BNIP3 in regulating mitochondrial function, such as in triggering apoptosis (Kim et al, 2002;Kubli et al, 2007;Cao et al, 2008). In the present study, BNIP3 like Cyto.…”

Section: Enlarged Mitochondria Confer Resistance To Apoptosismentioning

confidence: 79%

Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli

Chiche¹,

Rouleau²,

Gounon³

et al. 2009

Journal Cellular Physiology

114

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It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine- and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage.

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Section: Enlarged Mitochondria Confer Resistance To Apoptosismentioning

confidence: 79%

Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli

Chiche¹,

Rouleau²,

Gounon³

et al. 2009

Journal Cellular Physiology

114

View full text Add to dashboard Cite

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“…For example, BNip3 has been reported to interact directly with acetyl-CoA acyl transferase 2 (Acaa2), an enzyme involved in fatty acid oxidation in the mitochondrial matrix (6). However, BNip3 localizes to the outer mitochondrial membrane, making an interaction with a matrix protein such as Acaa2 unlikely.…”

Section: Discussionmentioning

confidence: 99%

BNip3 Regulates Mitochondrial Function and Lipid Metabolism in the Liver

Glick

Zhang

Beaton

et al. 2012

Molecular and Cellular Biology

200

185

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g BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. While the BNip3 protein is constitutively expressed in adult liver from fed mice, we have shown that its expression is superinduced by fasting of mice, consistent with a role in responses to nutrient deprivation. Loss of BNip3 resulted in increased lipid synthesis in the liver that was associated with elevated ATP levels, reduced AMP-regulated kinase (AMPK) activity, and increased expression of lipogenic enzymes. Conversely, there was reduced ␤-oxidation of fatty acids in BNip3 null liver and also defective glucose output under fasting conditions. These metabolic defects in BNip3 null liver were linked to increased mitochondrial mass and increased hepatocellular respiration in the presence of glucose. However, despite elevated mitochondrial mass, an increased proportion of mitochondria exhibited loss of mitochondrial membrane potential, abnormal structure, and reduced oxygen consumption. Elevated reactive oxygen species, inflammation, and features of steatohepatitis were also observed in the livers of BNip3 null mice. These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease. Modulation of mitochondrial mass is emerging as a major adaptive response to changes in energy balance arising from deficiencies in oxygen or glucose availability, among other nutrient stresses. For example, nutrient-sensitive changes in PGC-1␣ activity alter expression of genes required for mitochondrial biogenesis, in addition to genes required for fatty acid metabolism (17, 38). While mitochondrial biogenesis increases mitochondrial mass, this is countered by the role of mitophagy in targeting dysfunctional mitochondria for degradation at the autophagosome, resulting in reduced mitochondrial mass (28,29,70). Defects in autophagy have been linked to liver cancer (25,44,65) and have also been shown to promote hepatic insulin resistance (19, 67). However, this cannot be attributed to defective mitochondrial function, since autophagy-deficient liver also exhibits increased endoplasmic reticulum (ER) stress (67), protein aggregation (31), and defective lipidophagy (59). To date, a specific role for mitophagy in preventing hepatic steatosis or other liver pathologies has not been identified.Hypoxia modulates mitochondrial mass through both decreasing mitochondrial biogenesis (74) and increasing mitophagy (3,64,73). These effects are mediated by hypoxia-inducible factor (HIF) transcription factors, acting on the one hand to inhibit Myc-induced expression of PGC-1␤ (74) and on the other to induce expression of the mitochondrial proteins BNIP3 and NIX (3,4,64,73). Initial functional characterization of BNIP3 and NIX indicated that these proteins were loosely conserved members of the BH3-only subgroup of the Bcl-2 family of cell death regulators (7,8,52,68), and indeed, evidence from ischemia-reperfusion injury expe...

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“…Acetyl-CoA acyltransferase 2 (Acaa2) encodes for a mitochondrial matrix enzyme that catalyzes fatty acid β-oxidation occurring in the mitochondria. 98 NADH dehydrogenase (Ubiquinone) 1, α/β subcomplex, 1, 8 kDa (NDUFAB1) is also a mitochondrial protein subcomplex that is involved in the transfer of electrons from NADH to the respiratory chain. 99 Protein kinase, AMP-activated, α-2 catalytic subunit (PRKAA2) activates many catabolic pathways, including fatty acid metabolism, to ensure a high levels of ATP production.…”

Section: Lessons From Transcriptome Studies; Metabolic Gene Expressiomentioning

confidence: 99%