Newly discovered mechanism of mitochondrial dysfunction in obesity may drive insulin resistance and type 2 diabetes

A newly discovered mechanism that leads to liver dysfunction may be a key factor in type 2 diabetes and other metabolic disorders in individuals with obesity, according to a new study led by Harvard T.H. Chan School of Public Health.

The dysfunction identified—dysregulated hepatic coenzyme Q metabolism—leads to excessive reactive oxygen species (ROS) produced by mitochondria at a single specific site in an enzyme called complex I. The researchers say the discovery offers a potential path for new, precise treatments for metabolic diseases.

“Our findings provide the first step toward solving a complex problem in the field of metabolic disease research that has stood for three decades,” said corresponding author Gökhan S. Hotamisligil, James Stevens Simmons Professor of Genetics and Metabolism.

“Too much ROS has long been linked to obesity and age-related diseases, but precisely why, where, and how excess ROS is produced has remained unknown, limiting progress toward targeted therapeutics. This study helps close those knowledge gaps.”

The study is published in Nature.

Mitochondria metabolize nutrients and generate the building blocks needed to maintain metabolic homeostasis. During this process, mitochondria also generate ROS—molecules that, in small, controlled amounts, are essential to support normal body functions, but that can be harmful when produced in large quantities.

Excess ROS production is a known consequence of obesity, but its relationship to related metabolic disorders, such as type 2 diabetes, has been poorly understood.

To advance the understanding of mitochondrial ROS (mROS) generation—and its health consequences—the researchers zeroed in on the liver, a central organ for glucose and lipid homeostasis that has never been studied in detail in terms of mROS production. The study explored all possible sources of mROS in the liver from both lean and obese mice.

It found that the obese mice’s livers failed to produce proper amounts of coenzyme Q, a molecule essential to energy production. This defective coenzyme Q metabolism drives an unusual process called reverse electron transport (RET) that occurs in an enzyme called complex I, causing mitochondria to increase generation of ROS and, consequently, disrupt metabolism.

The researchers observed similar alterations in coenzyme Q metabolism when analyzing the genes and measuring coenzyme Q ratios in people with another metabolic disorder, fatty liver disease.

Prior studies had shown that eliminating ROS using broad antioxidants hasn’t improved outcomes in conditions like obesity, insulin resistance, and cardiovascular disease. The new study shifts the paradigm, said lead author Renata Goncalves, research associate in the Department of Molecular Metabolism.

“Instead of broad, unselective interventions, we systematically investigated the sources of mROS, and now know precisely where the excess is coming from and why,” she said.

“We’ve reframed the problem from a generalized to a site-specific phenomenon, so in the future, instead of broad-spectrum antioxidants, a tailored cocktail of compounds could be developed to effectively and safely reduce mROS, either through decreasing RET, increasing coenzyme Q levels, or both to treat metabolic diseases including type 2 diabetes.”