**Low VDAC1 Expression Is Associated with an Aggressive Phenotype and Reduced Overall Patient Survival in Cholangiocellular Carcinoma**

**René Günther Feichtinger 1,2,\*,**†**, Daniel Neureiter 3,**†**, Ralf Kemmerling 3, Johannes Adalbert Mayr 2, Tobias Kiesslich 4 and Barbara Kofler 1,2,**†


Received: 17 May 2019; Accepted: 4 June 2019; Published: 4 June 2019

**Abstract:** Cancer cells frequently exhibit dysfunctional oxidative phosphorylation (OXPHOS) and a concomitant increase in glycolytic flux. We investigated the expression of OXPHOS complex subunits and mitochondrial mass in 34 human cholangiocellular carcinomas (CCCs) and adjacent normal tissue by using tissue microarrays. In the tumor periphery, all OXPHOS complexes were reduced except complex I. In addition, significantly lower levels of complex IV were found at the tumor center (*p* < 0.0001). Mitochondrial mass, as indicated by VDAC1 expression, was significantly increased in CCCs compared to corresponding normal tissue (*p* < 0.0001). VDAC1 levels were inversely correlated with UICC (Union Internationale Contre le Cancer) cancer stage classification (*p* = 0.0065). Furthermore, significantly lower VDAC1 was present in patients with lymph node involvement (*p* = 0.02). Consistent with this, patients whose carcinomas expressed VDAC1 at low to moderate levels had significantly reduced survival compared to high expressors (*p* < 0.05). Therefore, low mitochondrial mass is associated with more aggressive CCC. These metabolic features are indicative of a Warburg phenotype in CCCs. This metabolic signature has potential therapeutic implications because tumors with low mitochondrial function may be targeted by metabolic therapies such as a high-fat, low-carbohydrate ketogenic diet.

**Keywords:** cholangiocellular carcinoma; mitochondria; energy metabolism; oxidative phosphorylation
