BNip3 Regulates Mitochondrial Function and Lipid Metabolism in the Liver

Abstract

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...

Mitochondrial autophagy: Origins, significance, and role of BNIP3 and NIX

“…Starvation induces BNIP3 expression in the liver, consistent with a role in hepatic function [119]. BNIP3 deficiency is associated with the accumulation of dysfunctional mitochondria in the liver, which is associated with an abnormal metabolic profile.…”

Recent insights into the function of autophagy in cancer

“…BNIP3, a BH3 domain-containing protein that, in some contexts, is considered a proapoptotic protein, likely plays a more important role in mitophagy than in the regulation of apoptosis during nutrient stress. BNIP3 is induced by nutrient deprivation in the liver, where it plays a role in promoting mitophagy and lipid oxidation (Glick et al 2012). BNIP3 expression is induced during the early stages of tumorigenesis but is lost in advanced cancer (Sowter et al 2001(Sowter et al , 2003Okami et al 2004;Abe et al 2005;Akada et al 2005;Erkan et al 2005).…”

BNIP3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

“…In terms of other metabolism-related effects in tissues, a group has reported that BNIP3-null mice livers have higher mitochondrial mass but impaired function compared with control mice [20]. Another study has shown that Bnip3 transcription is upregulated during brown fat adipogenesis [21].…”