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Granata 2023 MiP2023

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MiPschool 2023

Granata 2023 MiP2023

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


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 Km 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.

  1. Aubert, G., et al., The failing heart relies on ketone bodies as a fuel. Circulation, 2016. 133(8): p. 698-705.
  2. Forbes, J.M. and D.R. Thorburn, Mitochondrial dysfunction in diabetic kidney disease. Nature Reviews Nephrology, 2018. 14(5): p. 291-312.
  3. Robinson, A.M. and D.H. Williamson, Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiological reviews, 1980. 60(1): p. 143-187.
  4. Puchalska, P. and P.A. Crawford, Metabolic and signaling roles of ketone bodies in health and disease. Annual review of nutrition, 2021. 41: p. 49-77.
  5. Petrick, H.L., et al., In vitro ketone‐supported mitochondrial respiration is minimal when other substrates are readily available in cardiac and skeletal muscle. The Journal of Physiology, 2020. 598(21): p. 4869-4885.

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

O2k-Network Lab: DE Duesseldorf Roden M


Zweck E1,2,3, Piel S3, Chadt A2,4, Al-Hasani H2,4, Kelm M3,5, Szendrödi J1,2,6,7,8, Roden M1,2,5,6, Granata Cesare1,2
  1. Inst for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine Univ Düsseldorf, Düsseldorf, Germany
  2. German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, Germany
  3. Dept of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
  4. Inst for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine Univ Düsseldorf, Düsseldorf, Germany
  5. CARID, Cardiovascular Research Inst Düsseldorf, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
  6. Dept of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine Univ and Univ Hospital Düsseldorf, Düsseldorf, Germany
  7. Dept of Internal Medicine I and Clinical Chemistry, Univ Hospital Heidelberg, Germany
  8. Inst for Diabetes and Cancer (IDC) and Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Center München, Neuherberg, Germany
Corresponding author: [email protected]


Organism: Mouse 

Event: E2