Wohlfarter 2023 MiP2023
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].
- 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. https://doi.org/10.1203/00006450-200012000-00025
- Bhatta A, Dienemann C, Cramer P, Hillen HS. (2021) Structural basis of RNA processing by human mitochondrial RNase P. https://doi.org/10.1038/s41594-021-00637-y
- Zschocke J. (2012) HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. https://doi.org/10.1007/s10545-011-9415-4
- Boynton TO, Shimkets LJ. (2015) Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases. https://doi.org/10.1101/gad.268482.115
- 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. https://doi.org/10.1002/jimd.12433
- 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. https://doi.org/10.1007/s00018-022-04682-8
- Zschocke J, Byers PH, Wilkie AOM. (2023) Mendelian inheritance revisited: dominance and recessiveness in medical genetics. https://doi.org/10.1038/s41576-023-00574-0
Affiliations
- 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
- Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020 Innsbruck, Austria
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
- Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany
- Research Group Structure and Function of Molecular Machines, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Department of Paediatrics I (Inherited Metabolic Disorders), Medical University of Innsbruck, Innsbruck, Austria
- Cluster of Excellence ‘Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells’ (MBExC), University of Göttingen, Göttingen, Germany
- 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
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Event: E1