Respiratory complex I

Respiratory Complex I, also known as NADH:ubiquinone oxidoreductase, is the first enzyme complex in the Electron transport chain of Mitochondria. It plays a crucial role in Cellular respiration, facilitating the transfer of electrons from NADH to Coenzyme Q10 (ubiquinone), which is essential for the production of Adenosine triphosphate (ATP), the energy currency of the cell. This complex is one of the main sites for Proton gradient generation across the mitochondrial membrane, which drives ATP synthesis via ATP synthase.

Structure

Respiratory Complex I is a large protein complex with a mass of about 1 MDa (megaDalton) in mammals, comprising around 45 different subunits. Its structure can be divided into two main parts: a hydrophilic arm located in the mitochondrial matrix, which contains the sites for NADH dehydrogenation and ubiquinone reduction, and a hydrophobic arm embedded in the inner mitochondrial membrane, which facilitates proton translocation.

Function

The primary function of Complex I is to initiate the electron transport chain by oxidizing NADH, produced by the Krebs cycle and other metabolic pathways, and transferring two electrons to ubiquinone (CoQ10). This process is coupled with the translocation of four protons from the mitochondrial matrix to the intermembrane space, contributing to the proton motive force necessary for ATP synthesis. Complex I activity is tightly regulated, as its dysfunction can lead to excessive production of Reactive oxygen species (ROS), which can cause Oxidative stress and is associated with various Mitochondrial diseases and neurodegenerative disorders.

Pathology

Mutations in genes encoding the subunits of Complex I or factors involved in its assembly can lead to mitochondrial disorders, such as Leigh syndrome and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These conditions are characterized by a wide range of symptoms, including muscle weakness, neurological deficits, and organ failure, reflecting the essential role of Complex I in cellular energy metabolism.

Research and Clinical Implications

Inhibitors of Complex I, such as Rotenone and Piericidin A, are valuable tools in research for studying the mechanism of electron transport and the role of ROS in cell biology. Furthermore, understanding the structure and function of Complex I at a molecular level is crucial for developing therapeutic strategies for treating mitochondrial diseases and conditions associated with mitochondrial dysfunction.