What goes wrong in the cells of a baby with a mitochondrial complex III disease? It's complicated, but a new review article by the Kallijärvi research group at FHRC explains what we know about it so far.
In a recent review article, published in FEBS (Federation of European Biochemical Societies) Journal, Rishi Banerjee, Janne Purhonen and Jukka Kallijärvi discuss mitochondrial complex III function and the many metabolic pathways linked to it, the consequences of CIII deficiency in human patients, and how these diseases can be studied experimentally in the laboratory. The topic of the review is directly related to the work of the research group, led by docent Jukka Kallijärvi and prof. emerita Vineta Fellman at FHRC, studying GRACILE syndrome, a severe CIII deficiency disease of newborns.
Mitochondria are organelles that dwell inside almost all animal and plant cells, including yours. They are like a combination of a factory and a power plant, in which many different nutrients a.k.a food-derived small molecules become oxidized or “burned” and their energy stored in simpler energetic molecules more easily usable within the cell in biochemical reactions. Oxidization means that a molecule – in this case a nutrient-derived molecule - loses electrons. These electrons then flow like electricity through and between four big protein complexes (CI to CIV) comprising the electron transport chain, being carried part of the way by a small lipid-like molecule called coenzyme Q (CoQ).
The respiratory complexes sit in the inner membrane of mitochondria, a sheet of lipids that is itself an efficient insulator. The complexes have inbuilt pumps that operate with the electricity and, instead of liquid, pump protons. The pumped protons are like a reservoir of water that then flows back though turbines of the power plant. However, instead of producing again electricity, the turbines synthesize adenosine triphosphate (ATP), a handy high-energy molecule.
Studying these processes in experimental models may help find new treatments for mitochondrial disaeases.
Complex III is the evolutionarily most ancient of the mitochondrial respiratory complexes. Apart from proton translocation, complex III has a unique special task: it re-oxidizes CoQ, in other words takes away the two electrons that CoQ has received during the oxidation of nutrient molecules, making CoQ again ready to accept more electrons. Altogether nine mitochondrial enzymes use CoQ as an electron acceptor. This means that if CIII is for some reason out of order, these enzymes may also not work properly. Many of these enzymes produce useful molecules needed in manufacture of a wide variety of other molecules that are needed in, for example, as building blocks or RNA and DNA. They are also important in the oxidation of fatty acids and one of the most abundant amino acid in the body, proline. One important task of these mitochondrial enzymes is the detoxification of hydrogen sulphide, a toxic gas produced by gut bacteria and as a side product of normal metabolism in most cells.
In humans, gene mutations that impair CIII function cause CIII deficiencies, such as GRACILE syndrome, severe inborn metabolic diseases that normally start in early childhood. These diseases are mostly untreatable and their disease mechanisms poorly understood, hindering the development of therapies. Recent work by the Kallijärvi/Fellman group and others has suggested that decreased energy (ATP) production is less important as a disease mechanism in CIII deficiencies than previously thought while the other CoQ/CIII-dependent metabolic routes are more important. Studying these processes in experimental models such as mice and cultured cells may help find new treatments for mitochondrial disaeases.
Read the full article here.
Jukka Kallijärvi & Simon Granroth
Reference:
Banerjee R, Purhonen J, Kallijärvi J. The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology. FEBS J. (2021) doi: 10.1111/febs.16164
