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Clinical MedicineMetabolism
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10.1172/jci.insight.178645
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
Find articles by Wibom, R. in: JCI | PubMed | Google Scholar
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
Find articles by Bruhn, H. in: JCI | PubMed | Google Scholar
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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Végvári, Á.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
Find articles by Käll, L. in: JCI | PubMed | Google Scholar
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
Find articles by Taylor, R. in: JCI | PubMed | Google Scholar
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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Wedell, A.
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1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
5NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
6Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden.
7Laboratory for Biomedical Mass Spectrometry, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Address correspondence to: Robert W. Taylor, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom. Phone: 44.191.2824375; Email: robert.taylor@ncl.ac.uk. Or to: Anna Wedell, Department of Molecular Medicine and Surgery, Inborn errors of Endocrinology and Metabolism group, Karolinska Institutet, 171 76 Stockholm, Sweden. Phone: 46.8.52480000; Email: anna.wedell@ki.se. Or to: Anna Wredenberg, Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, 171 77 Stockholm, Sweden. Phone: 46.8.12371425; Email: anna.wredenberg@ki.se.
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Published September 17, 2024 - More info
Published in Volume 9, Issue 20 on October 22, 2024
Abstract
BACKGROUND. Mitochondrial diseases belong to the group of inborn errors of metabolism (IEM), with a prevalence of 1 in 2,000–5,000 individuals. They are the most common form of IEM, but, despite advances in next-generation sequencing technologies, almost half of the patients are left genetically undiagnosed.
METHODS. We investigated a cohort of 61 patients with defined mitochondrial disease to improve diagnostics, identify biomarkers, and correlate metabolic pathways to specific disease groups. Clinical presentations were structured using human phenotype ontology terms, and mass spectrometry–based proteomics was performed on primary fibroblasts. Additionally, we integrated 6 patients carrying variants of uncertain significance (VUS) to test proteomics as a diagnostic expansion.
RESULTS. Proteomic profiles from patient samples could be classified according to their biochemical and genetic characteristics, with the expression of 5 proteins (GPX4, MORF4L1, MOXD1, MSRA, and TMED9) correlating with the disease cohort, thus acting as putative biomarkers. Pathway analysis showed a deregulation of inflammatory and mitochondrial stress responses. This included the upregulation of glycosphingolipid metabolism and mitochondrial protein import, as well as the downregulation of arachidonic acid metabolism. Furthermore, we could assign pathogenicity to a VUS in MRPS23 by demonstrating the loss of associated mitochondrial ribosome subunits.
CONCLUSION. We established mass spectrometry–based proteomics on patient fibroblasts as a viable and versatile tool for diagnosing patients with mitochondrial disease.
FUNDING. The NovoNordisk Foundation, Knut and Alice Wallenberg Foundation, Wellcome Centre for Mitochondrial Research, UK Medical Research Council, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children.
IntroductionInborn errors of metabolism (IEM) comprise a group of over 800 disorders marked by the toxic accumulation or depletion of essential metabolites (1, 2). Many of these disorders are monogenic and affect pathways related to carbohydrate, lipid, amino acid, organic acid, peroxisomal, or lysosomal metabolism. Mitochondrial disorders stand out as a heterogeneous subgroup of IEM, where the primary defect interferes with mitochondrial aerobic energy conversion. The clinical presentation of these disorders is diverse, affecting various organs, including the brain, skeletal muscle, heart, and liver — either in isolation or as part of a multisystem phenotype — manifesting at any age (3, 4).
To date, over 400 genes are linked to mitochondrial disease, caused by pathogenic variants in either the nuclear (nDNA) or mitochondrial (mtDNA) genome (5). Many of these variants disrupt the assembly or function of the oxidative phosphorylation (OXPHOS) system, a multicomplex system responsible for synthesizing the vast majority of cellular ATP. Over 90 subunits are organized into 5 complexes comprising a respiratory chain (CI–IV) coupled to an ATP synthase (CV). Most OXPHOS subunits and over 130 proteins required for assembly are encoded on the nuclear genome. An additional 13 essential OXPHOS subunits, 22 tRNAs, and 2 rRNAs, required for mitochondrial translation, are encoded on mtDNA (6).
Conventionally thought only to include variants affecting factors involved in OXPHOS function and assembly, primary mitochondrial disorders now also include a broader spectrum of functions, including mitochondrial morphology and dynamics, coenzyme Q10 biosynthesis, proteases, and a wider field of mitochondrial gene expression (7). Generally, mitochondrial diseases have profound consequences for affected individuals and their families, often resulting in severe, chronic, debilitating diseases that are difficult to manage. The lack of effective treatment options frequently leads to a challenging and uncertain future for those affected.
Historically, most patients were diagnosed by their clinical and biochemical presentations but rarely received a definitive genetic diagnosis. Integrating next-generation sequencing into accredited diagnostic services nearly 15 years ago dramatically improved gene discovery for IEM, but, despite combining clinical, laboratory, and genetic analysis, around 50% of investigated patients remain undiagnosed (8). Often, this can be attributed to a failure to classify variants of uncertain significance (VUS), both in coding and noncoding regions, such as promoter and enhancer regions. Although incorporating transcriptomic analysis into diagnostic pipelines has improved the success rate (9), almost half of patients still fail to receive a definite genetic diagnosis, and further improvements and approaches are required.
Recent advances in mass spectrometry allow for the quantitative detection of large numbers of proteins, potentially adding an additional layer to the diagnosis of patients with IEM. Recent reports integrating multiomics approaches into healthcare have demonstrated the feasibility of this strategy (10–15). Furthermore, besides supporting patient diagnostics by providing instant validation of genomic variants, proteomics also increases our understanding of mitochondrial biology disease mechanisms and can further be used to monitor and validate treatment strategies.
Here, we performed mass spectrometry–based label-free proteomics on primary fibroblasts from a cohort of 67 patients with diagnosed or suspected mitochondrial disease and 17 individuals in a control group to advance diagnostics, identify biomarkers, and gain insights into disease mechanisms. Our data reveal that, despite their heterogeneity, certain clinical symptoms prevail within specific groups of mitochondrial disease. Furthermore, we identify several factors consistently altered in all disease groups, suggesting they could act as potential biomarkers for mitochondrial disease pathology. Importantly, we demonstrate that proteomics can be used to stratify into individual mitochondrial disease groups and even support accurate diagnosis in individual cases.
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