Research Article For reprint orders, please contact: reprints@futuremedicine.com Relationship of single nucleotide polymorphisms and haplotype interaction of mitochondrial unfolded protein response pathway genes with head and neck cancer Malik Waqar Ahmed ‡,1 , Ishrat Mahjabeen ‡,1 , Shazma Gul 1 , Anum Khursheed 1 , Azhar Mehmood 1 & Mahmood Akhtar Kayani* ,1 1 Cancer Genetics & Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad, Park Road Tarlai Kalan, Islamabad Pakistan *Author for correspondence: Tel.: +92 321 5357981; mkayani@comsats.edu.pk ‡ Authors contributed equally Aim: In this study, we evaluated the effect of selected polymorphisms of mitochondrial unfolded pro- tein response (UPR mt ) pathway in 500 head and neck cancer (HNC) patients and 500 healthy controls from Pakistan. Materials & methods: The experiments were conducted using tetra-ARMS PCR followed by DNA sequencing. Results: Multivariate analysis showed that AA genotype of rs3782116 showed fvefold, GG genotype of rs6598072 approximately twofold and CC genotype of rs4946936 and TT genotype of rs12212067 showed twofold increased risk of HNC. Furthermore, haplotype analysis showed that certain haplotypes of UPR mt pathway single nucleotide polymorphisms have signifcant association with increased HNC risk. Conclusion: These results show that genetic aberrations in UPR mt pathway genes have associa- tion with increased HNC risk and can be an indicator of advance clinical outcome especially invasion and metastasis. First draft submitted: 26 June 2019; Accepted for publication: 4 September 2019; Published online: 25 October 2019 Keywords: clinical outcome • haplotype analysis • HNC • metastasis • UPR mt mechanism Mitochondria is the major source for production of ATP and reactive oxygen species (ROS) [1]. This produced ROS can play a bifacial role in context of mitochondrial integrity. Low levels of ROS are beneficial, act as signaling molecules or upregulate protective responses [2,3]. Whereas, ROS have the damaging aspect at higher concentrations. Increased ROS in the mitochondria can cause the mtDNA damage, which in turn cause mutations in mitochondrial encoded protein and misfolding in the structure [4]. Increased accumulation of misfolded/aggregated protein if exceeds the limit of mitochondrial quality control machinary, cells activate unfolded protein response (UPR mt ), a mitochondria-to-nucleus crosstalk [5]. The UPR mt pathway has three axis that are activated upon mitochondrial protein misfolding/aggregations. The UPR mt activates the CHOP/ATF5/ATF4 axis, which lead to the induction of the chaperonins, chaperones and proteases to increase the folding capacity inside mitochondria [6]. The second axis of UPR mt pathway is the estrogen receptor α axis which acts via AKT and ROS-dependent phosphorylation of ERα, causing induction of NRF1 [7]. This in turn leads to increased protease levels, modulation of respiration levels and enhanced proteasome activity to increase the control capacity of protein quality [8]. The UPR mt involves three important mitochondrial molecules such as SIRT3, FOXO3a and SOD2 in its third axis [9]. SIRT3 leads to the deacetylation and relocalization of FOXO3a to the nucleus, where it activates SOD2 and catalase as part of an antioxidant response. SIRT3 axis do not regulate protease and chaperons [9]. SIRT3, an important deacetylation gene in mitochondria, plays a critical role in moderating reactive oxygen species (ROS) and regulates ROS in matrix of mitochondria. SIRT3 functions as a tumor promoter, as it is also responsible for keeping ROS level under a certain threshold compatible with cell viability and proliferation [10]. However, loss of SIRT3 function is associated with the development of a permissive phenotype for tumor development due to hyperacetylation of mitochondrial proteins and cells show increased oxidative stress, which contributes toward Future Oncol. (2019) 15(33), 3819–3829 ISSN 1479-6694 3819 10.2217/fon-2019-0365 C  2019 Future Medicine Ltd