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The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.

ROS generation is regulated and maintained at moderate levels necessary for normal cellular signaling processes in a healthy cell. However, cancer cells possess a higher antioxidant capacity, enabling ROS maintenance at a level that triggers pro-tumorigenic pathways without causing cancer cell death. Thus, cancer cells have an altered redox environment, with a high ROS production rate counterbalancing a high ROS scavenging rate. This unique feature of cancer cells makes them more sensitive to alteration in ROS levels than normal cells. The inhibitory compounds that hamper regular electron flow in the ETC can also trigger the mitochondrial cell death pathway. For instance, ETC inhibitors, such as metformin, resveratrol, and fenretinide, disrupt the normal functioning of the respiratory complexes. This induces elevated ROS production to a level that exceeds the antioxidant capacity of the cancer cells, resulting in their death.

Complex I is inhibited by metformin, an AMP-activated protein kinase that blocks mitochondrial respiratory functions and induces programmed cell death in several types of cancer cells, including pancreatic and breast cancer cells. Mutations in complex II, although rare, can lead to tumors of the carotid body-sensory organ of the peripheral nervous system.

Besides cancer, abnormal activity or deficiency in electron transport chain complexes has been linked to human neurodegenerative diseases. For example, in Parkinson's disease, there is a lack of function of complex I. Similarly, defects in complex II have been linked to Huntington's disease.

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