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Wohlfarter 2023 MiP2023

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MiPschool 2023

Wohlfarter 2023 MiP2023

Wohlfarter Yvonne
The Janus-faced nature of HSD10 in cardiolipin biosynthesis and mitochondrial function.

Link: MiP2023 Obergurgl AT

Wohlfarter Yvonne (2023)

Event: MiP2023 Obergurgl AT

Authors: Wohlfarter Yvonne, Eidelpes R, Yu RD, Sailer S, Koch Jakob, Karall Daniela, Scholl‑Buergi S, Amberger A, Hillen HS, Zschocke J, Keller Markus A Introduction: Human 17β-Hydroxysteroid dehydrogenase 10 (HSD10) is a crucial enzyme located in mitochondria that participates in isoleucine catabolism and is part of the mitochondrial RNase P complex [1,2]. Mutations in the HSD10B17 gene have been linked to HSD10 disease, which causes progressive cardiomyopathy and cognitive function loss [3]. Recently, HSD10 has been reported to possess a phospholipase C-like activity towards cardiolipins, which are essential mitochondrial membrane lipids involved in various processes such as super-complex assembly, cristae formation, and apoptotic signaling cascades [4]. The transacylase tafazzin is remodeling cardiolipin side chains, and its deficiency leads to high levels of monolyso-cardiolipins and abnormal cardiolipin patterns [5].
Methods: To explore the role of HSD10 in cardiolipin homeostasis, we carried out a comprehensive analysis of cardiolipin profiles in different cellular contexts by means of LC-MS/MS [6]: We investigated the impact of HSD10 knockdown in wild-type cells, in a tafazzin-deficient background, and in fibroblasts derived from HSD10-deficient patients. Additionally, by supplementation with fatty acids such as linoleic acid and palmitic acid we simulated different lipid environments.
Results and Discussion: We found no evidence for the enzyme function of HSD10 to be involved in cardiolipin homeostasis in all conditions examined [6]. Thus, its previously reported cardiolipin cleaving function is likely to be regarded as an in vitro artefact. However, the HSD10's structural importance in the mitochondrial RNase P complex underscores its essential role in cellular function [7]. We show that the enzyme has evolved with significant evolutionary constraints to maintain this structure, possibly at the expense of achieving a high degree of substrate specificity and reaction rates [6].

  1. Zschocke J, Ruiter JPN, Brand J, et al (2000) Progressive Infantile Neurodegeneration Caused by 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency: A Novel Inborn Error of Branched-Chain Fatty Acid and Isoleucine Metabolism.
  2. Bhatta A, Dienemann C, Cramer P, Hillen HS. (2021) Structural basis of RNA processing by human mitochondrial RNase P.
  3. Zschocke J. (2012) HSD10 disease: clinical consequences of mutations in the HSD17B10 gene.
  4. Boynton TO, Shimkets LJ. (2015) Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases.
  5. Oemer G, Koch J, Wohlfarter Y, Lackner K, Gebert REM, Geley S, et al. (2022) The lipid environment modulates cardiolipin and phospholipid constitution in wild type and tafazzin-deficient cells.
  6. Wohlfarter Y, Eidelpes R, Yu RD, Sailer S, Koch J, Karall D, et al. (2022) Lost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism.
  7. Zschocke J, Byers PH, Wilkie AOM. (2023) Mendelian inheritance revisited: dominance and recessiveness in medical genetics.


Wohlfarter Y1, Eidelpes R2, Yu RD3,4, Sailer S1, Koch J1, Karall D5, Scholl‑Bürgi S5, Amberger A1, Hillen HS3,4,6, Zschocke J1, Keller MA1
  1. Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020 Innsbruck, Austria
  2. Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  3. Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
  4. Research Group Structure and Function of Molecular Machines, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
  5. Department of Paediatrics I (Inherited Metabolic Disorders), Medical University of Innsbruck, Innsbruck, Austria
  6. Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC), University of Göttingen, Göttingen, Germany


Event: E2