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Pharmacology & Chemical Biology Seminar Series
3/28/2024 - 12:00 PM-1:00 PM
“Hepatic Ubiquinone Imbalance Drives Reverse Electron Transport and Pathological mROS in Obesity”

Renata Goncalves, PhD 
Research Associate
Harvard School of Public Health

Mitochondrial reactive oxygen species (mROS) are central to physiology. While excess mROS production has been associated with several disease states, its precise sources, regulation, and mechanism of generation in vivo remain unknown, limiting translational efforts. Here we show that in obesity, hepatic ubiquinone (Q) synthesis is impaired, which raises the QH2/Q ratio, driving excessive mROS production via reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo we demonstrated that RET is critical for metabolic health. In patients with steatosis, the hepatic Q biosynthetic program is also suppressed, and the QH2/Q ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
 
Thomas E. Starzl Biomedical Science Tower
1395 Conference Room
200 Lothrop St
Pittsburgh, PA 15213
Contact
Melanie Hoffner

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