Delivery of antioxidants to liver mitochondria

A new drug delivery system delivers an antioxidant directly to mitochondria in the liver, mitigating the effects of oxidative stress.

Damage to the liver induced by acetaminophen (dotted blue outlines) is almost completely mitigated by CoQ₁₀-MITO-Porter (right), compared to the effect of phosphate buffered saline (left) and direct administration of CoQ₁₀(center). (Mitsue Hibino, et al. Scientific Reports. May 10, 2023).

Mitochondria are microscopic organelles found within cells, and are well-known as the “powerhouse of the cell.” They are by far the largest producer of the molecule adenosine triphosphate (ATP), which provides energy to many processes in living cells. The process by which mitochondria synthesize ATP generates a large amount of reactive oxygen species (ROS), chemical groups that are highly reactive. 

In a healthy cell, the ROS are controlled by the mitochondria; however, when this balance is lost, the excess ROS damages the mitochondria and subsequently cells and tissues. This phenomenon, known as oxidative stress, can cause premature aging and disease. The ROS that cause oxidative stress can be controlled by antioxidants.

A research team led by Professor Yuma Yamada, Distinguished Professor Hideyoshi Harashima and Assistant Professor Mitsue Hibino at Hokkaido University have developed a system to deliver antioxidants to mitochondria to mitigate the effects of excess ROS. Their findings were published in Scientific Reports.

“We previously developed a drug delivery system which we named CoQ₁₀-MITO-Porter,” explained Hibino. “This system consists of the antioxidant molecule Coenzyme Q₁₀ (CoQ₁₀)—which is also required by mitochondria for ATP production—encapsulated by a lipid nanoparticle that would target mitochondria. In this study, we aimed to test if this system could work in living organisms.” 

CoQ₁₀-MITO-Porter (green sphere with red and blue protrusions) is taken up by liver cells (hepatocytes) and targets mitochondria. The delivery of CoQ₁₀ reduces the excess ROS produced by mitochondria and thus reduces oxidative stress. (Mitsue Hibino, et al. Scientific Reports. May 10, 2023).

Variations of the formula for the synthesis of CoQ₁₀-MITO-Porter were tested, and their structures were examined with electron microscopy. CoQ₁₀-MITO-Porter was administered to mice models with acetaminophen-induced liver damage. Acetaminophen overdoses cause excess ROS in mitochondria, which in turn damages cells in the liver. CoQ₁₀-MITO-Porter was transported primarily to the liver and measurably reduced the damage caused by ROS. A further discovery was that downsized CoQ₁₀-MITO-Porter particles with more efficient packaging of CoQ₁₀ were more effective at treating liver damage than the original formulation.

“Our study has shown that the MITO-Porter system we developed can be used to deliver CoQ₁₀ to the liver, making it an important therapeutic strategy against conditions that cause oxidative stress,” concluded Yamada. “Our future work will focus on elucidating the mechanism responsible for the therapeutic effect of CoQ₁₀.”

Yuma Yamada (left), Mitsue Hibino (center) and Hideyoshi Harashima (right), key authors of the study (Photo: Yuma Yamada).

Original Article:

Mitsue Hibino, et al. A System that Delivers an Antioxidant to Mitochondria for the treatment of Drug-Induced Liver Injury. Scientific Reports. May 10, 2023.

DOI: 10.1038/s41598-023-33893-7

Funding:

This work was supported a grant from the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (MEXT); Japan Science and Technology Agency (JST) FOREST (JPMJFR203X9); and a grant from the KOSE Cosmetology Research Foundation.

Contacts:

Professor Yuma Yamada

Faculty of Pharmaceutical Sciences

Hokkaido University

Tel: +81-11-706-3735

Email: u-ma[at]pharm.hokudai.ac.jp

Assistant Professor Mitsue Hibino

Faculty of Engineering

Hokkaido University
Tel: +81-11-706-6745

Email: mit5ue[at]eng.hokudai.ac.jp

Sohail Keegan Pinto (International Public Relations Specialist)

Public Relations & Communications Division

Office of Public Relations and Social Collaboration

Hokkaido University

Tel: +81-11-706-2186

Email: en-press[at]general.hokudai.ac.jp

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