Mitochondria are double-membraned organelles found inside nearly all human cells, popularly known as the “powerhouses” because they generate the vast majority of cellular energy in the form of adenosine triphosphate (ATP). This energy production is achieved through a highly efficient process called oxidative phosphorylation (OXPHOS). Beyond energy, mitochondria manage many aspects of cell health, including signaling and programmed cell death. When a normal cell transforms into a cancer cell, it fundamentally alters how its mitochondria function and integrate into the cell’s survival strategy. This organelle is therefore a central node of dysfunction that drives malignant progression.
The Cancer Cell’s Energy Rewiring
Cancer cells typically undergo a metabolic shift, prioritizing an inefficient process known as aerobic glycolysis, or the Warburg Effect. This involves rapidly converting large amounts of glucose into lactate in the cytosol, even when ample oxygen is available for the more efficient mitochondrial OXPHOS pathway. Glycolysis generates only two ATP molecules per glucose molecule, compared to up to 30 from OXPHOS. This metabolic choice is a trade-off, favoring speed and the creation of essential cellular building blocks required for rapid growth over maximizing energy output.
The metabolic rerouting diverts glycolytic intermediates into branching pathways necessary for proliferation. For instance, intermediates like 3-phosphoglycerate are siphoned off to feed the serine biosynthesis pathway, contributing to the production of nucleotides and lipids. High glucose uptake also pushes carbon into the pentose phosphate pathway, generating the NADPH reducing power needed for synthesizing fatty acids and neutralizing oxidative stress. This reliance on glycolysis allows the cancer cell to quickly generate the biomass needed for continuous cell division.
The enzyme lactate dehydrogenase A (LDHA) is upregulated in many tumors, converting pyruvate into lactate. This conversion is necessary to regenerate NAD+, a coenzyme required to keep the upstream glycolytic pathway active. The resulting lactate is often secreted, creating an acidic microenvironment that can promote tumor invasion and suppress local immune responses.
Regulating Cell Suicide
Mitochondria function as the central checkpoint for the intrinsic pathway of apoptosis, the cell’s programmed mechanism for self-destruction. This process is governed by the BCL-2 protein family, whose members balance pro-death and pro-survival signals at the mitochondrial outer membrane. When a cell detects irreparable damage, pro-apoptotic effector proteins, primarily BAX and BAK, are activated. These effectors then cluster together to form pores in the mitochondrial outer membrane.
Mitochondrial outer membrane permeabilization (MOMP) occurs when the membrane is breached. Pro-apoptotic factors stored in the mitochondrial intermembrane space, most notably Cytochrome C, are released into the cytosol. Cytochrome C then triggers a cascade of enzymes called caspases, which dismantle the cell in a controlled manner. Cancer cells evade this fate by manipulating the BCL-2 family proteins to inhibit MOMP.
Tumor cells frequently overexpress anti-apoptotic members, such as BCL-2, BCL-xL, and MCL-1. These pro-survival proteins bind directly to and sequester the pro-death BAX and BAK proteins, preventing them from forming pores. By maintaining high levels of these inhibitory proteins, cancer cells become addicted to this survival mechanism and ignore the damage signals that would normally force a healthy cell to commit suicide.
Genetic Contributions to Malignancy
Mitochondrial DNA (mtDNA) is a small, circular piece of genetic material distinct from nuclear DNA. Unlike nuclear DNA, mtDNA is highly susceptible to mutation due to its lack of protective histones and the proximity of the Electron Transport Chain, which constantly generates DNA-damaging reactive oxygen species (ROS). This results in a mutation rate for mtDNA that is significantly higher than that of nuclear DNA.
These mutations are not random, with a frequent occurrence in the non-coding D-loop region, which controls mtDNA replication and transcription. Functional mutations are often observed in the genes that encode subunits of the respiratory complexes, particularly Complex I (NADH dehydrogenase). Such changes can alter the efficiency of energy generation and, paradoxically, increase the production of ROS.
While severe mitochondrial dysfunction can be lethal, a moderate increase in ROS caused by specific mtDNA mutations can act as a signaling molecule that promotes tumorigenesis and metastatic potential. This effect is often observed when a cell carries a mixed population of mutant and wild-type mtDNA, a state known as heteroplasmy. Inherited mitochondrial traits, such as specific mitochondrial haplogroups, are being investigated as factors that may influence susceptibility or resistance to developing certain types of cancer.
Exploiting Mitochondrial Weaknesses for Treatment
The metabolic and survival reliance of cancer cells on mitochondrial dysfunction has made the organelle a promising therapeutic target. One approach targets the Warburg Effect using metabolic inhibitors aimed at the enzyme LDHA. Compounds such as FX-11 prevent the conversion of pyruvate to lactate, forcing cancer cells to use the mitochondrial OXPHOS pathway for energy and disrupting the biosynthetic pathways needed for proliferation.
A second strategy involves restoring the cell’s ability to initiate apoptosis through drugs known as BH3 mimetics. The FDA-approved drug Venetoclax is a prime example, functioning as a selective inhibitor of the anti-apoptotic protein BCL-2. Venetoclax binds to BCL-2’s inhibitory groove, freeing the pro-apoptotic proteins BAX and BAK to form pores in the mitochondrial membrane. This mechanism triggers programmed cell death in BCL-2-dependent hematological malignancies like Chronic Lymphocytic Leukemia.
A third class of agents, known as Mitocans, directly targets the mitochondrial machinery. These therapies frequently utilize a positively charged molecule, such as the Triphenylphosphonium (TPP+) cation, to deliver the therapeutic payload into the mitochondria. Since many cancer cells exhibit a higher negative mitochondrial membrane potential than healthy cells, the TPP+ tag causes selective accumulation of the drug within the mitochondria. This targeted delivery allows the use of drugs that inhibit respiratory complexes, forcing the cancer cell toward energy crisis and collapse.