Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle

Guillaume Tournaire; Shauni Loopmans; Steve Stegen; Gianmarco Rinaldi; Guy Eelen; Sophie Torrekens; Karen Moermans; Peter Carmeliet; Bart Ghesquière; Bernard Thienpont; Sarah-Maria Fendt; Nick van Gastel; Geert Carmeliet

doi:10.1016/j.celrep.2022.111105

Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle

Cell Rep. 2022 Jul 26;40(4):111105. doi: 10.1016/j.celrep.2022.111105.

Affiliations

¹ Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
² Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
³ Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
⁴ Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium.
⁵ Metabolomics Expertise Center, Department of Oncology, KU Leuven/VIB Center for Cancer Biology Leuven, Leuven, Belgium.
⁶ Laboratory of Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁷ de Duve Institute, UC Louvain, Brussels, Belgium.
⁸ Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, O&N1bis Herestraat 49, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium. Electronic address: [email protected].

Abstract

A functional electron transport chain (ETC) is crucial for supporting bioenergetics and biosynthesis. Accordingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell proliferation. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmacological inhibition of complex III of the ETC in skeletal stem and progenitor cells induces glycolysis side pathways and reroutes the tricarboxylic acid (TCA) cycle to regenerate NAD⁺ and preserve cell proliferation. These metabolic changes also culminate in increased succinate and 2-hydroxyglutarate levels that inhibit Ten-eleven translocation (TET) DNA demethylase activity, thereby preserving self-renewal and multilineage potential. Mechanistically, mitochondrial malate dehydrogenase and reverse succinate dehydrogenase activity proved to be essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the metabolic plasticity of skeletal stem and progenitor cells allows them to bypass ETC blockade and preserve their self-renewal.

Keywords: CP: Metabolism; CP: Stem cell research; NAD regeneration; TCA rerouting; TET activity; cell-based regenerative medicine; electron transport chain; metabolic plasticity; proliferation; reverse succinate dehydrogenase; self-renewal; skeletal stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Citric Acid Cycle*
Energy Metabolism / physiology
Mitochondria* / metabolism
Respiration