The article by Douglas C. Wallace discusses the critical role of mitochondria in cancer cells, challenging the conventional wisdom that mitochondrial dysfunction is essential for cancer development. Instead, it highlights that mutations in mitochondrial genes do not inactivate energy metabolism but alter the mitochondrial bioenergetic and biosynthetic state, which communicates with the nucleus through retrograde signaling to modulate various cellular processes. These alterations can reprogram adjacent stromal cells to optimize the cancer cell environment, leading to the activation of out-of-context programs involved in development, stress response, wound healing, and nutritional status. The author reviews the historical context of Otto Warburg's observation that cancer cells produce excessive lactate in the presence of oxygen, a phenomenon known as "aerobic glycolysis." Despite extensive research, the role of mitochondrial oxidative phosphorylation (OXPHOS) in cancer remained unclear until recent insights into mitochondrial biology. Mitochondria, the symbiotic partners of the nuclear-cytoplasmic organism, play a crucial role in coordinating energy production and distribution based on calorie and oxygen availability. They control vital cellular parameters such as energy production, redox status, ROS generation, cytosolic calcium levels, and apoptosis initiation. The article also discusses the importance of mtDNA mutations in cancer, including those affecting succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase 1 (IDH1) and IDH2. These mutations can alter metabolic pathways, influence nuclear signaling, and affect chromatin structure, contributing to cancer development. Additionally, the article explores the impact of mitochondrial enzyme defects, such as SDH and FH mutations, on cellular redox balance and ROS production. The review further examines the role of mitochondrial ROS in cancer, the regulation of acetyl-CoA, glutaminolysis, and the interaction between p53 and mitochondria. It highlights the importance of retrograde signaling, where mitochondrial alterations reprogram the nucleus, and the "reverse Warburg effect," where cancer cells and stromal cells cooperate to maintain glycolysis in the stromal cells, enhancing FDG accumulation in cancer detection. Finally, the article emphasizes the need for further research into mitochondrial biology and genetics to understand the diverse bioenergetic alterations in cancer cells and the complex interactions between cancer cells and their microenvironment.The article by Douglas C. Wallace discusses the critical role of mitochondria in cancer cells, challenging the conventional wisdom that mitochondrial dysfunction is essential for cancer development. Instead, it highlights that mutations in mitochondrial genes do not inactivate energy metabolism but alter the mitochondrial bioenergetic and biosynthetic state, which communicates with the nucleus through retrograde signaling to modulate various cellular processes. These alterations can reprogram adjacent stromal cells to optimize the cancer cell environment, leading to the activation of out-of-context programs involved in development, stress response, wound healing, and nutritional status. The author reviews the historical context of Otto Warburg's observation that cancer cells produce excessive lactate in the presence of oxygen, a phenomenon known as "aerobic glycolysis." Despite extensive research, the role of mitochondrial oxidative phosphorylation (OXPHOS) in cancer remained unclear until recent insights into mitochondrial biology. Mitochondria, the symbiotic partners of the nuclear-cytoplasmic organism, play a crucial role in coordinating energy production and distribution based on calorie and oxygen availability. They control vital cellular parameters such as energy production, redox status, ROS generation, cytosolic calcium levels, and apoptosis initiation. The article also discusses the importance of mtDNA mutations in cancer, including those affecting succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase 1 (IDH1) and IDH2. These mutations can alter metabolic pathways, influence nuclear signaling, and affect chromatin structure, contributing to cancer development. Additionally, the article explores the impact of mitochondrial enzyme defects, such as SDH and FH mutations, on cellular redox balance and ROS production. The review further examines the role of mitochondrial ROS in cancer, the regulation of acetyl-CoA, glutaminolysis, and the interaction between p53 and mitochondria. It highlights the importance of retrograde signaling, where mitochondrial alterations reprogram the nucleus, and the "reverse Warburg effect," where cancer cells and stromal cells cooperate to maintain glycolysis in the stromal cells, enhancing FDG accumulation in cancer detection. Finally, the article emphasizes the need for further research into mitochondrial biology and genetics to understand the diverse bioenergetic alterations in cancer cells and the complex interactions between cancer cells and their microenvironment.