There is a renewed interest in tumorigenesis provoked by glycolysis and prosurvival autophagy following the mitochondrial permeability transition during cell death. To investigate such mitochondrial dysfunction, we have developed a multiscale model by integrating the dynamic behaviors of essential oncogenic proteins, cells, and their microenvironment. We found that 1) the concentration of cellular ATP (adenosine triphosphate) available during the autophagy-related processes is a critical factor in determining tumorigenesis; 2) mitochondrial aging rate has a significant influence on this tumorigenic effect, 3) specific hypoxic and oxidative stresses work cooperatively for tumorigenesis during cell death. We conclude that the cellular mitochondrial status is critical in triggering tumorigenesis during the cell death process, particularly under harsh microenvironments.