Granata 2023 MiP2023

Granata 2023 MiP2023

Novel mitochondrial respiration protocols reveal organ-specific reliance on ketone body metabolism in mice.

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Granata Cesare (2023)

Event: MiP2023 Obergurgl AT

Authors: Zweck Elric, Piel Sarah, Chadt A, Al-Hasani H, Kelm M, Szendroedi Julia, Roden Michael, Granata Cesare

Introduction: Ketone bodies (KB) are important substrates for the heart, particularly during heart failure [1], kidney [2], brain, skeletal muscle, and other organs [3]. Despite their significant role in health and disease [4], very limited research is available investigating KB-linked ATP production in mammalian tissues [5]; moreover, no optimized protocols exist to assess the interplay of key enzymes involved in ketolysis and their respective contribution to OXPHOS capacity.
Methods: β-hydroxybutyrate (HBA)- and acetoacetate (ACA)-linked mitochondrial respiration was assessed in the heart left ventricle (LV), kidney, liver, brain, and soleus of ~18-24-week-old C57BL/6J female mice (n=6-8). A novel protocol combining KB-linked and complex I (CI)+CII-linked mitochondrial respiration was also devised.
Results and discussion: The K_m for HBA was similar (~1 mM) in all tested organs. However, maximal HBA-linked respiration was different between organs (p<0.001), i.e., greater in the LV and liver (~32 pmol O₂·s^-1·mg^-1), and lowest in the brain (5.2 pmol O₂·s^-1·mg^-1). This protocol allows to determine β-hydroxybutyrate dehydrogenase activity in the liver. The Km for ACA and maximal ACA-linked respiration were greater in the kidney compared to the other tested organs (all p<0.050). Our novel KB+CI+CII combined respiration protocol indicated that the KB contribution to maximal respiration is 2- to 4-fold greater in the kidney (37.4 %) compared to all other organs (all p<0.050), confirming the kidney’s reliance on KB metabolism [2]. Taken together, our novel protocols demonstrate an organ-specific response of mitochondrial respiration to different KBs.

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• Keywords: ketone body, mitochondrial respiration, ketolysis, mitochondria, high-resolution respirometry

• O2k-Network Lab: DE Duesseldorf Roden M

Affiliations

Zweck E^1,2,3, Piel S³, Chadt A^2,4, Al-Hasani H^2,4, Kelm M^3,5, Szendrödi J^1,2,6,7,8, Roden M^1,2,5,6, Granata Cesare^1,2

Inst for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine Univ Düsseldorf, Düsseldorf, Germany
German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Germany
Dept of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
Inst for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine Univ Düsseldorf, Düsseldorf, Germany
CARID, Cardiovascular Research Inst Düsseldorf, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
Dept of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
Dept of Internal Medicine I and Clinical Chemistry, Univ Hospital Heidelberg, Germany
Inst for Diabetes and Cancer (IDC) and Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Center München, Neuherberg, Germany

Corresponding author: cesare.granata@ddz.de

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Organism: Mouse

Event: Oral