19.6:
Electron Transport Chain: Complex I and II
The mitochondrial inner membrane constitutes a series of five multi-subunit enzyme complexes responsible for transport of electrons from high-energy carriers, NADH, and FADH2, in an energetically downhill sequence, to a low-energy electron acceptor- oxygen.
The first complex-NADH-Q oxidoreductase, is the largest enzyme complex in the series, transferring electrons from NADH to coenzyme Q.
This L-shaped complex includes 45 different subunits, of which the mitochondrial genome encodes seven. Its major catalytic components are the NADH-binding site, the primary electron acceptor- FMN, and multiple iron-sulfur clusters.
The second complex is part of both the citric acid cycle and the electron transport chain. It transports electrons from succinate to FADH2 and finally to coenzyme Q via iron-sulphur clusters. This complex is therefore known as the succinate-Q reductase.
It is a nuclear-encoded tetramer with two hydrophilic subunits – A and B. Subunit-A is a flavoprotein with FAD cofactor and a succinate binding site. Subunit-B is an iron-sulfur protein with three iron-sulfur clusters. The other two subunits – C and D are hydrophobic integral-membrane proteins that contain a Q-binding site.
19.6:
Electron Transport Chain: Complex I and II
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.
Suggested Reading
- Rohlena, Jakub, Lan-Feng Dong, Stephen J. Ralph, and Jiri Neuzil. "Anticancer drugs targeting the mitochondrial electron transport chain." Antioxidants & redox signaling 15, no. 12 (2011): 2951-2974.
- Dong, Lanfeng, and Jiri Neuzil. "Targeting mitochondria as an anticancer strategy." Cancer Communications 39, no. 1 (2019): 1-3.
- Hroudová, Jana, Namrata Singh, and Zdeněk Fišar. "Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer’s disease." BioMed research international 2014 (2014).
- Reczek, Colleen R., and Navdeep S. Chandel. "The two faces of reactive oxygen species in cancer." (2017).
- Wojtovich, Andrew P., C. Owen Smith, Cole M. Haynes, Keith W. Nehrke, and Paul S. Brookes. "Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel." Biochimica et Biophysica Acta (BBA)-Bioenergetics 1827, no. 5 (2013): 598-611.