Hepatocellular carcinoma (HCC) is one of the fastest-rising causes of cancer-related mortality in the United States. The biggest risk factor for developing HCC is viral infection (HBV and HCV). Other factors include non- alcoholic fatty liver disease (NAFLD), alcohol use, and obesity/metabolic syndromes. Genetics also plays an important role in the development and progression of HCC. Notably, HCC burden is disproportionately expressed among different ethnic groups; the incidence and mortality rates are much higher in Hispanics than in non-Hispanic whites (NHW) for both genders, particularly in South Texas where Hispanics are the fastest- growing population. Moreover, Hispanics with Hepatitis C Virus (HCV) infection are at a significantly higher risk of developing cirrhosis and HCC compared to NHW with HCV. One major target of HCV proteins is the mitochondria. Mitochondrial DNA (mtDNA) alterations and mitochondrial dysfunction are implicated in various types of cancer, including HCC. A human mtDNA haplogroup is defined by unique sets of mtDNA polymorphisms, reflecting mutations accumulated by a discrete lineage. The distribution of mitochondrial haplogroups in the Hispanic population differs greatly from that of the NHW population, which may have some influcence on the higher incidence of HCC in Hispanics. Based on these facts and our previous studies, we seek to determine whether and how distinct mitochondrial haplogroups, mitochondrial dysfunction, and HCV infection (as well as the interactions between these factors) impact HCC tumorigenesis and progresion. The hypothesis tested here is that (1) Hispanic-specific mitochondrial haplogroup(s) and possible associated reduced OXPHOS provide a mitochondrial background that favors HCC progresion and (2) that the interactions between HCV proteins and mitochondrial machinery compromise OXPHOS and critical aspects of mitochondrial pathways, leading to HCC tumorigenesis. Our recent breakthroughs include the following: (1) the establishment of Hispanic HCC cell lines and (2) the generation of an inducible, dosage-dependent, non- mitochondrial-conflicting expression system, which will enable us to test the overarching hypothesis. We will generate cybrids with a Hispanic HCC nuclear background but different mitochondrial haplogroups and investigate mitochondrial function and tumorigenesis in these cybrids. We will also test the hypotheses that (1) reduced mitochondrial function increases HCC tumorigenesis while enhanced OXPHOS activity will decrease HCC tumorigenesis and (2) a Hispanic-specific background will sensitize the cells to HCV-mediated HCC tumorigenesis. Finally, taking advantage of big data about HCC patients in public databases and our unique access to our institute’s large liver Biobank with Hispanic HCC patient samples, we will complement these molecular investigations with bioinformatics and human epidemiology studies to verify associations between mitochondrial genetics, mitochondrial function...