Ehinger 2016 Nat Commun: Difference between revisions
No edit summary |
No edit summary Β |
||
(14 intermediate revisions by 4 users not shown) | |||
Line 1: | Line 1: | ||
{{Publication | {{Publication | ||
|title=Ehinger JK, Piel S, Ford R, Karlsson M, SjΓΆvall F, Frostner EΓ
, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, ElmΓ©r E (2016) Cell-permeable succinate prodrugs bypass mitochondrial | |title=Ehinger JK, Piel S, Ford R, Karlsson M, SjΓΆvall F, Frostner EΓ
, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, ElmΓ©r E (2016) Cell-permeable succinate prodrugs bypass mitochondrial Complex I deficiency. Nat Commun 7:12317. https://doi.org/10.1038/ncomms12317 | ||
|info=[https://www.ncbi.nlm.nih.gov/pubmed/27502960 PMID: 27502960 Open Access] | |info=[https://www.ncbi.nlm.nih.gov/pubmed/27502960 PMID: 27502960 Open Access] Β»[[File:O2k-brief.png|36px|link=http://wiki.oroboros.at/images/b/ba/Ehinger_2016_Nat_Commun_O2k-brief.pdf |O2k-brief]] | ||
|authors=Ehinger JK, Piel S, Ford R, Karlsson M, Sjoevall F, Asander FE, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E | |authors=Ehinger JK, Piel S, Ford R, Karlsson M, Sjoevall F, Asander FE, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E | ||
|year=2016 | |year=2016 | ||
|journal=Nat Commun | |journal=Nat Commun | ||
|abstract=Mitochondrial | |abstract=Mitochondrial Complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. | ||
|keywords=Drug delivery, Energy metabolism, Metabolism | |keywords=Drug delivery, Energy metabolism, Metabolism, MitoKit-CII | ||
|mipnetlab=SE Lund Elmer E | |mipnetlab=SE Lund Elmer E | ||
}} | }} | ||
[[File:O2k-brief.png|36px|left]] | |||
== O2k-brief == | |||
::::Β» [[O2k-brief |List of O2k-Publications presented as O2k-brief]] | |||
== Cited by == | |||
{{Template:Cited by Gnaiger 2020 BEC MitoPhysiology}} | |||
{{Labeling | {{Labeling | ||
|area=Respiration, Patients, Pharmacology;toxicology | |area=Respiration, Patients, Pharmacology;toxicology | ||
|tissues=Heart, Blood cells | |diseases=Inherited | ||
|injuries=Mitochondrial disease | |||
|preparations=Intact cells | |tissues=Heart, Blood cells, Fibroblast | ||
|preparations=Permeabilized tissue, Intact cells | |||
|enzymes=Complex I, Complex II;succinate dehydrogenase | |enzymes=Complex I, Complex II;succinate dehydrogenase | ||
|topics=Substrate | |topics=Substrate | ||
|couplingstates=OXPHOS, | |couplingstates=OXPHOS, ET | ||
| | |pathways=S | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional= | |additional=MitoKit-CII, SUIT-010 O2 ce-pce D050, JP, SE, MitoEAGLE blood cells data, O2k-brief, BEC 2020.1 | ||
}} | }} |
Latest revision as of 18:51, 8 April 2022
Ehinger JK, Piel S, Ford R, Karlsson M, SjΓΆvall F, Frostner EΓ , Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, ElmΓ©r E (2016) Cell-permeable succinate prodrugs bypass mitochondrial Complex I deficiency. Nat Commun 7:12317. https://doi.org/10.1038/ncomms12317 |
Β» PMID: 27502960 Open Access Β»
Ehinger JK, Piel S, Ford R, Karlsson M, Sjoevall F, Asander FE, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E (2016) Nat Commun
Abstract: Mitochondrial Complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. β’ Keywords: Drug delivery, Energy metabolism, Metabolism, MitoKit-CII
β’ O2k-Network Lab: SE Lund Elmer E
O2k-brief
Cited by
- Gnaiger E et al β MitoEAGLE Task Group (2020) Mitochondrial physiology. Bioenerg Commun 2020.1. doi:10.26124/bec:2020-0001.v1.
Labels: MiParea: Respiration, Patients, Pharmacology;toxicology
Pathology: Inherited
Stress:Mitochondrial disease
Tissue;cell: Heart, Blood cells, Fibroblast Preparation: Permeabilized tissue, Intact cells Enzyme: Complex I, Complex II;succinate dehydrogenase Regulation: Substrate Coupling state: OXPHOS, ET Pathway: S HRR: Oxygraph-2k
MitoKit-CII, SUIT-010 O2 ce-pce D050, JP, SE, MitoEAGLE blood cells data, O2k-brief, BEC 2020.1