Mitochondria, often called the “powerhouses” of the cell, are involved in the life and death of our cells. Their primary function is to generate adenosine triphosphate (ATP), the energy that fuels cellular activities. These organelles are also integrated into the cell’s regulatory networks, influencing processes from growth to programmed cell death. This role in maintaining normal cellular function means that when mitochondrial processes are disrupted, it can contribute to diseases, including cancer.
The Standard Role of Mitochondria in Healthy Cells
Mitochondria are best known for their role in energy production. Through a process called oxidative phosphorylation, they convert chemical energy from food into ATP. This system takes place across the inner membrane of the mitochondrion, which is folded into structures called cristae to maximize the surface area for these reactions. The process generates the vast majority of the energy our cells need to perform their specialized tasks.
Beyond supplying energy, mitochondria are central to a safety mechanism known as programmed cell death, or apoptosis. Healthy organisms rely on apoptosis to eliminate old, damaged, or unnecessary cells in a controlled manner. When a cell receives signals indicating it’s time to die, mitochondria release a protein called cytochrome c. This release triggers a process that systematically dismantles the cell from the inside out.
Mitochondria also regulate the levels of calcium within a cell, a process important for signaling pathways. They also produce and manage reactive oxygen species (ROS), which in small amounts act as signaling molecules but can cause damage at high levels. By managing these metabolic pathways, mitochondria act as hubs that help maintain cellular balance and respond to various stressors, ensuring the health of the organism.
Mitochondrial Alterations in Cancer Cells
In cancer cells, the function and structure of mitochondria undergo significant changes. A well-documented alteration is a metabolic shift known as the Warburg effect. Unlike healthy cells that prefer efficient oxidative phosphorylation, many cancer cells switch to a less efficient process called aerobic glycolysis to produce energy. This allows cancer cells to rapidly generate ATP and the molecular building blocks necessary for rapid cell proliferation.
This metabolic adaptation is accompanied by changes in the physical characteristics of the mitochondria. In many types of cancer, mitochondria can become fragmented, appearing smaller and more numerous than in healthy cells. This process, known as mitochondrial fission, is believed to contribute to tumor progression. The number of mitochondria per cell can also change to meet the energy demands of a growing tumor or as the cell becomes more reliant on glycolysis.
Mitochondria contain their own circular DNA, known as mitochondrial DNA (mtDNA), which is separate from the nuclear DNA. This mtDNA is susceptible to mutations because it lacks many of the robust DNA repair mechanisms found in the cell’s nucleus. Mutations in mtDNA can disrupt the proteins involved in oxidative phosphorylation, encouraging the cell’s reliance on glycolysis. Accumulations of these mutations are found in various cancers and are thought to contribute to tumor progression.
How Altered Mitochondria Drive Cancer Progression
The changes within cancer cell mitochondria are not merely byproducts; they actively fuel the cancer’s survival and spread. A primary consequence is the evasion of programmed cell death. By modifying proteins and pathways that control the mitochondrial outer membrane, cancer cells can prevent the release of cytochrome c. This silences the internal self-destruct signal, allowing malignant cells to survive and proliferate despite significant DNA damage.
This resistance to cell death is coupled with the ability to fuel metastasis, the process of cancer spreading to other parts of the body. For a cancer cell to metastasize, it must detach from the primary tumor, survive in the bloodstream, and establish a new colony in a distant organ. This process is energy-intensive, and altered mitochondria provide the necessary ATP and metabolic flexibility. This allows cancer cells to adapt to different nutrient conditions and stress levels encountered during their journey.
Dysfunctional mitochondria also contribute to cancer progression by changing the signals they send to the rest of the cell. Stressed or damaged mitochondria can produce an excess of reactive oxygen species (ROS). The moderately elevated levels found in cancer cells act as signaling molecules that promote cell proliferation, survival, and angiogenesis—the formation of new blood vessels to supply the tumor. This sustained signaling creates a pro-tumorigenic environment that supports growth and invasion.
Exploiting Mitochondrial Weaknesses for Cancer Treatment
The reliance of cancer cells on altered mitochondrial processes presents opportunities for targeted therapies. One strategy involves targeting the specific metabolic pathways that cancer cells use to survive. Researchers are developing drugs that inhibit enzymes in the glycolytic pathway, aiming to cut off the cancer cell’s primary source of energy and building blocks. This approach is designed to starve cancer cells while having a minimal impact on healthy cells.
Another therapeutic avenue focuses on reactivating the disabled apoptosis machinery within cancer cells. Since many cancers evade cell death by altering proteins that regulate mitochondrial pore formation, treatments are designed to restore this balance. Drugs known as BH3 mimetics work by inhibiting the anti-apoptotic proteins overexpressed in cancer cells. This frees up pro-apoptotic proteins to signal for the release of cytochrome c, pushing the cancer cell to undergo programmed cell death.
The oxidative stress within cancer cells can also be turned into a vulnerability. Because their mitochondria are already producing high levels of ROS, cancer cells operate close to a toxic threshold. Certain therapeutic agents are designed to exacerbate this oxidative stress, pushing the mitochondria past a point of no return. This strategy aims to selectively kill cancer cells by overwhelming their antioxidant defense systems, leaving healthy cells relatively unharmed.