Extended Data Fig. 7: Model Overview of Coenzyme Q (CoQ) Synthesis Imbalance in Obese Livers.
From: CoQ imbalance drives reverse electron transport to disrupt liver metabolism
Illustration of the model detailing the impact of CoQ synthesis deficiency on the CoQH2/CoQ ratio, resulting in increased mitochondrial reactive oxygen species (mROS) production via reverse electron transport (RET) and subsequent impairment of glucose homeostasis (black boxes). Different genetic and pharmacological interventions were utilized to modulate specific nodes within the model, ranging from CoQ synthesis and levels to the direct generation of mROS via RET. Approaches highlighted in blue indicate interventions that improved glucose homeostasis, while those in red denote interventions that worsen it. To investigate whether obesity-driven CoQ deficiency contributed to the observed alterations in CoQH2/CoQ ratio, obese mice were supplemented with CoQ10. This treatment restored CoQ10 levels, lowered CoQH2/CoQ ratio, and mitigated mROS production via RET, thereby improving glucose homeostasis. Similarly, manipulating CoQ redox state through ectopic expression of Ciona intestinalis alternative oxidase (Aox) in the livers of obese mice resulted in decreased mROS via RET and improved glucose homeostasis. The point mutation in the ND6 gene (ND6P25L) was found to directly hinder complex I-mediated mROS generation via RET, these mice had enhanced glucose homeostasis in high-fat diet. Conversely, impairing CoQ biosynthesis in lean mice (via pdss2 knockdown) or directly inducing mROS via RET with mitoPQ led to compromised glucose homeostasis. This figure provides a comprehensive overview of the intricate interplay between hepatic CoQ synthesis, redox state, mROS production via RET, and their collective impact on glucose homeostasis in the context of obesity. Created with BioRender.com.
