Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome

Valerian E Kagan; Yulia Y Tyurina; Karolina Mikulska-Ruminska; Deena Damschroder; Eduardo Vieira Neto; Alessia Lasorsa; Alexander A Kapralov; Vladimir A Tyurin; Andrew A Amoscato; Svetlana N Samovich; Austin B Souryavong; Haider H Dar; Abu Ramim; Zhuqing Liang; Pablo Lazcano; Jiajia Ji; Michael W Schmidtke; Kirill Kiselyov; Aybike Korkmaz; Georgy K Vladimirov; Margarita A Artyukhova; Pushpa Rampratap; Laura K Cole; Ammanamanchi Niyatie; Emma-Kate Baker; Jim Peterson; Grant M Hatch; Jeffrey Atkinson; Jerry Vockley; Bernhard Kühn; Robert Wessells; Patrick C A van der Wel; Ivet Bahar; Hülya Bayir; Miriam L Greenberg

doi:10.1038/s42255-023-00926-4

Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome

Valerian E Kagan^*, Yulia Y Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A Kapralov, Vladimir A Tyurin, Andrew A Amoscato, Svetlana N Samovich, Austin B Souryavong, Haider H Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K VladimirovMargarita A Artyukhova, Pushpa Rampratap, Laura K Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C A van der Wel, Ivet Bahar, Hülya Bayir, Miriam L Greenberg^*

^*Corresponding author for this work

Solid State Nuclear Magnetic Resonance

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.

Original language	English
Pages (from-to)	2184–2205
Number of pages	22
Journal	Nature Metabolism
Volume	5
Early online date	23-Nov-2023
DOIs	https://doi.org/10.1038/s42255-023-00926-4
Publication status	Published - Dec-2023

Keywords

NMR
SSNMR
Mitochondria

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Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndromeFinal publisher's version, 8.76 MBLicence: Taverne

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Kagan, V. E., Tyurina, Y. Y., Mikulska-Ruminska, K., Damschroder, D., Vieira Neto, E., Lasorsa, A., Kapralov, A. A., Tyurin, V. A., Amoscato, A. A., Samovich, S. N., Souryavong, A. B., Dar, H. H., Ramim, A., Liang, Z., Lazcano, P., Ji, J., Schmidtke, M. W., Kiselyov, K., Korkmaz, A., ... Greenberg, M. L. (2023). Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome. Nature Metabolism, 5, 2184–2205. https://doi.org/10.1038/s42255-023-00926-4

@article{7616d0e54e2949c0b9f83a125d7da13b,

title = "Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome",

abstract = "Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.",

keywords = "NMR, SSNMR, Mitochondria",

author = "Kagan, {Valerian E} and Tyurina, {Yulia Y} and Karolina Mikulska-Ruminska and Deena Damschroder and {Vieira Neto}, Eduardo and Alessia Lasorsa and Kapralov, {Alexander A} and Tyurin, {Vladimir A} and Amoscato, {Andrew A} and Samovich, {Svetlana N} and Souryavong, {Austin B} and Dar, {Haider H} and Abu Ramim and Zhuqing Liang and Pablo Lazcano and Jiajia Ji and Schmidtke, {Michael W} and Kirill Kiselyov and Aybike Korkmaz and Vladimirov, {Georgy K} and Artyukhova, {Margarita A} and Pushpa Rampratap and Cole, {Laura K} and Ammanamanchi Niyatie and Emma-Kate Baker and Jim Peterson and Hatch, {Grant M} and Jeffrey Atkinson and Jerry Vockley and Bernhard K{\"u}hn and Robert Wessells and {van der Wel}, {Patrick C A} and Ivet Bahar and H{\"u}lya Bayir and Greenberg, {Miriam L}",

note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s42255-023-00926-4",

language = "English",

volume = "5",

pages = "2184–2205",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer Nature",

}

Kagan, VE, Tyurina, YY, Mikulska-Ruminska, K, Damschroder, D, Vieira Neto, E, Lasorsa, A, Kapralov, AA, Tyurin, VA, Amoscato, AA, Samovich, SN, Souryavong, AB, Dar, HH, Ramim, A, Liang, Z, Lazcano, P, Ji, J, Schmidtke, MW, Kiselyov, K, Korkmaz, A, Vladimirov, GK, Artyukhova, MA, Rampratap, P, Cole, LK, Niyatie, A, Baker, E-K, Peterson, J, Hatch, GM, Atkinson, J, Vockley, J, Kühn, B, Wessells, R, van der Wel, PCA, Bahar, I, Bayir, H & Greenberg, ML 2023, 'Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome', Nature Metabolism, vol. 5, pp. 2184–2205. https://doi.org/10.1038/s42255-023-00926-4

TY - JOUR

T1 - Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome

AU - Kagan, Valerian E

AU - Tyurina, Yulia Y

AU - Mikulska-Ruminska, Karolina

AU - Damschroder, Deena

AU - Vieira Neto, Eduardo

AU - Lasorsa, Alessia

AU - Kapralov, Alexander A

AU - Tyurin, Vladimir A

AU - Amoscato, Andrew A

AU - Samovich, Svetlana N

AU - Souryavong, Austin B

AU - Dar, Haider H

AU - Ramim, Abu

AU - Liang, Zhuqing

AU - Lazcano, Pablo

AU - Ji, Jiajia

AU - Schmidtke, Michael W

AU - Kiselyov, Kirill

AU - Korkmaz, Aybike

AU - Vladimirov, Georgy K

AU - Artyukhova, Margarita A

AU - Rampratap, Pushpa

AU - Cole, Laura K

AU - Niyatie, Ammanamanchi

AU - Baker, Emma-Kate

AU - Peterson, Jim

AU - Hatch, Grant M

AU - Atkinson, Jeffrey

AU - Vockley, Jerry

AU - Kühn, Bernhard

AU - Wessells, Robert

AU - van der Wel, Patrick C A

AU - Bahar, Ivet

AU - Bayir, Hülya

AU - Greenberg, Miriam L

PY - 2023/12

Y1 - 2023/12

N2 - Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.

AB - Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.

KW - NMR

KW - SSNMR

KW - Mitochondria

U2 - 10.1038/s42255-023-00926-4

DO - 10.1038/s42255-023-00926-4

M3 - Article

C2 - 37996701

SN - 2522-5812

VL - 5

SP - 2184

EP - 2205

JO - Nature Metabolism

JF - Nature Metabolism

ER -

Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome

Abstract

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