Pancreatic cancer remains a major unsolved health problem as a result of limited success rate of chemo- or radiation therapy. New treatment strategies are urgently needed to improve the survival rate of patients with this type of malignancy. Mitochondrial energy metabolism is currently recognized as a promising treatment target in a wide spectrum of cancers. Recent studies demonstrated that mitochondrial oxidative phosphorylation (OXPHOS) is vital for tumor cells not solely as a source of ATP, but even more importantly, to supply building blocks for their anabolic needs [1, 2]. A number of drugs targeting respiratory chain complexes, particularly complex I (CI) inhibitors, are being evaluated in clinical trials for different types of neoplastic diseases, including pancreatic cancer [3, 4]. Among them, metformin, a biguanide derivative, has attracted considerable attention since it is already used in the clinic for treatment of type 2 diabetes. Furthermore, mitochondrially targeted metformin (MitoMet) was developed to augment the therapeutic activity of this mild CI inhibitor. This modification resulted in markedly increased efficacy to target mitochondrial CI and in elevated tumor-suppressing effects in mouse models of pancreatic cancer [5, 6]. However, due to considerable genetic as well as metabolic heterogeneity of pancreatic tumors, determining the factors governing responsiveness to complex I inhibitors is of great importance in order to select patients who will best benefit from this type of therapy.