TY - JOUR
T1 - Glyoxylate reductase
T2 - Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate
AU - Garrelfs, Sander F.
AU - Chornyi, Serhii
AU - te Brinke, Heleen
AU - Ruiter, Jos
AU - Groothoff, Jaap
AU - Wanders, Ronald J. A.
N1 - Funding Information: This work was funded by the Amsterdam University Medical Centers; personal PhD Scholarship Sander F. Garrelfs, Metakids (grant ID: 2019‐04‐UMD), and Stofwisselkracht. Publisher Copyright: © 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2024/3
Y1 - 2024/3
N2 - Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
AB - Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
KW - glyoxylate metabolism
KW - hydroxyproline
KW - hyperoxaluria
KW - mitochondria
KW - oxalate
KW - peroxisomal disorders
KW - peroxisomes
UR - http://www.scopus.com/inward/record.url?scp=85181930123&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12711
DO - https://doi.org/10.1002/jimd.12711
M3 - Article
C2 - 38200664
SN - 0141-8955
VL - 47
SP - 280
EP - 288
JO - Journal of inherited metabolic disease
JF - Journal of inherited metabolic disease
IS - 2
ER -