Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
| Autor: | Kyle L. Hoehn, Jerry R. Greenfield, Warren Kaplan, Ganesh Kolumam, James G. Burchfield, David E. James, Nolan J. Hoffman, Daniel L. T Chen, Jean Yh Yang, Ciana Diskin, Kelsey H. Fisher-Wellman, Sean J. Humphrey, Ghassan J. Maghzal, Kristen C. Thomas, Benjamin L. Parker, James R. Krycer, Zora Modrusan, Rima Chaudhuri, Roland Stocker, Daniel J. Fazakerley, Pengyi Yang, Dorit Samocha-Bonet, Christopher C. Meoli, Mark J. Cowley |
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| Přispěvatelé: | Fazakerley, Daniel J [0000-0001-8241-2903], James, David E [0000-0001-5946-5257], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mitochondrial Diseases Mouse Ubiquinone medicine.medical_treatment Respiratory chain Adipose tissue Mitochondrion Mice chemistry.chemical_compound Adipocytes Insulin Glucose homeostasis Biology (General) Muscle Weakness Chemistry Superoxide Muscles General Neuroscience human biology food and beverages General Medicine Oxidants Mitochondria 3. Good health Adipose Tissue Medicine Research Article Human medicine.medical_specialty QH301-705.5 Science Sensitivity and Specificity General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Insulin resistance Internal medicine medicine Animals Humans Human Biology and Medicine General Immunology and Microbiology Coenzyme Q Cell Biology medicine.disease 030104 developmental biology Endocrinology Coenzyme Q – cytochrome c reductase Ataxia |
| Zdroj: | eLife, Vol 7 (2018) eLife |
| Popis: | Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance. eLife digest After we eat, our blood sugar levels increase. To counteract this, the pancreas releases a hormone called insulin. Part of insulin’s effect is to promote the uptake of sugar from the blood into muscle and fat tissue for storage. Under certain conditions, such as obesity, this process can become defective, leading to a condition known as insulin resistance. This condition makes a number of human diseases more likely to develop, including type 2 diabetes. Working out how insulin resistance develops could therefore unveil new treatment strategies for these diseases. Mitochondria – structures that produce most of a cell’s energy supply – appear to play a role in the development of insulin resistance. Mitochondria convert nutrients such as fats and sugars into molecules called ATP that fuel the many processes required for life. However, ATP production can also generate potentially harmful intermediates often referred to as ‘reactive oxygen species’ or ‘oxidants’. Previous studies have suggested that an increase in the amount of oxidants produced in mitochondria can cause insulin resistance. Fazakerley et al. therefore set out to identify the reason for increased oxidants in mitochondria, and did so by analysing the levels of proteins and oxidants found in cells grown in the laboratory, and mouse and human tissue samples. This led them to find that concentrations of a molecule called coenzyme Q (CoQ), an essential component of mitochondria that helps to produce ATP, were lower in mitochondria from insulin-resistant fat and muscle tissue. Further experiments suggested a link between the lower levels of CoQ and the higher levels of oxidants in the mitochondria. Replenishing the mitochondria of the lab-grown cells and insulin-resistant mice with CoQ restored ‘normal’ oxidant levels and prevented the development of insulin resistance. Strategies that aim to increase mitochondria CoQ levels may therefore prevent or reverse insulin resistance. Although CoQ supplements are readily available, swallowing CoQ does not efficiently deliver CoQ to mitochondria in humans, so alternative treatment methods must be found. It is also of interest that statins, common drugs taken by millions of people around the world to lower cholesterol, also lower CoQ and have been reported to increase the risk of developing type 2 diabetes. Further research is therefore needed to investigate whether CoQ might provide the link between statins and type 2 diabetes. |
| Databáze: | OpenAIRE |
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