Summary
Abnormal mitochondrial oxidative phosphorylation (OXPHOS) is key to the pathogenesis of several cardiometabolic diseases. The ketone bodies (KBs), β-hydroxybutyrate (HBA) and acetoacetate (ACA), are critical for tissue-specific energy metabolism under various pathophysiological conditions. However, robust methods quantifying their contribution as substrates for OXPHOS are lacking. Here, we first established comprehensive high-resolution respirometry protocols for assessing the differential contributions of HBA, ACA, and related ketolytic enzymes to OXPHOS in translational studies in mice and humans. We then utilized these protocols to demonstrate (i) organ-specific differences in KB-driven mitochondrial respiration in mice, (ii) lower KB-driven mitochondrial respiration in liver of humans with steatosis, skeletal muscle of humans with diabetes and in kidney of diet-induced obese mice, as well as (iii) higher mitochondrial KB utilization capacity in mouse and human failing heart. These results highlight organ-specific roles of KB metabolism in cardiometabolic diseases and shall help to identify novel targets in these pathways.
Competing Interest Statement
AP receives research funding from Abiomed outside of this work. RaW is employed by Abiomed. RoW reports lecture fees from Novo Nordisk, Sanofi-Aventis, Boehringer Ingelheim and Eli Lilly, and served on the advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis, Eli Lilly, and NovoNordisk. MR is currently on scientific advisory boards of Astra Zeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Madrigal, Merck-MSD, Novo Nordisk, and Target RWE, and has received support for investigator-initiated studies from Boehringer Ingelheim, Novo Nordisk and Nutricia/Danone. The other authors declare no competing interests.
