Mitoproteases display an essential role in the preservation of mitochondrial homeostasis under regular and stress conditions. These enzymes perform tightly regulated proteolytic reactions by which they participate in mitochondrial protein traffcking, processing and activation of proteins, protein quality control, regulation of mitochondrial biogenesis, control of mitochondrial dynamics, mitophagy, and apoptosis. In this chapter, we have revised the physiological functions of the intrinsic mitochondrial proteases, analyzing their roles in the different compartments of this organelle and their connection to human pathology, primarily cancer, neurodegenerative disorders, and multisystemic diseases.

Given the extensive history of cancer, the history of patient-derived xenograft (PDX) models is also diffcult to fully recapitulate. In particular, this task is complicated by the irregularity with which PDX models were designated. The current use of “PDX cancer models” is a relatively recent addition to the lexicon. However, the general concept of PDX models—i.e., the transplantation of human cancers into animal models—can be found throughout the chronicles of cancer research. However, it wasn’t until the discovery of host immunity and its crucial role in graft survival that the idea of serial transplantation could be realized. Therefore, in order to better reflect the nature of its history, the term “human tumor models” will be used in place of “PDX models,” except when appropriate. Finally, it is important to also mention the existence of the other labels that have been used, including, but not limited to, “human tumor xenografts,” “xenopatients,” heterotransplant tumor models,” “heterotransplanted human tumors,” and “transplantable tumor models.”

Pancreatic cancer (PC) is one of the leading causes of cancer deaths worldwide. It is the fourth leading cause of cancer-related death in both men and women in the United States and has <10% 5-year overall survival rate for all stages . Worldwide, PC is the eighth leading cause of cancer death in men (about 138,100 deaths annually) and the ninth in women (about 127,900 deaths annually). In general it affects more individuals residing in the Western and industrialized parts of the world with the highest incidence reported in New Zealand, Black American and Hawaiians and the lowest incidence reported among people living in Nigeria and India . Based on data obtained from the surveillance epidemiology and end results (SEER) database, the incidence and death rate of PC is 12.4 and 10.9 per 100,000 men and women per year, respectively. In the United States, an estimated 53,070 people will be diagnosed with PC in the year 2016, and 41,780 people will die secondary to it . PC occurs less commonly before age 45, but its incidence rises sharply thereafter with more than half of the patients over 70 years at diagnosis. As the average lifespan is expected to increase in the future, it is likely that PC would become more prevalent. Over 85% of exocrine PCs are adenocarcinomas with other variants making up the rest . Majority of PCs are idiopathic in nature with exception of few cases where an actual risk factor could be identifed. Some of the nonfamilial risk factors that have been identifed which may contribute to the development of PC include smoking, alcohol, diabetes, impaired glucose metabolism, insulin resistance, obesity, infections, coffee and non-blood group ‘O’. Age is considered one of the most common risk factors with an obvious dramatic increase in incidence of PC as one gets older. Racial factor may play a role in development and outcome of PC.