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<p>Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (<i>Taz</i>), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in <i>Taz</i> deteriorate mitochondrial respiration, Ca<sup>2+</sup>-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with <i>Taz</i>-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in <i>Taz</i>-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in <i>Taz</i>-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in <i>Taz</i>-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with <i>Taz</i>-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac <i>Taz</i>-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in <i>Taz</i>-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.</p>

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Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Elsie Kajese,
  • Malte Hachmann,
  • Katharina J. Ermer,
  • Manuela Erk,
  • Lin Alhasaan,
  • Michael Kohlhaas,
  • Heike Bömmel,
  • Lisa Berberich,
  • Christopher Carlein,
  • Hanna Eberl,
  • Katrin Streckfuß-Bömeke,
  • Leticia Prates Roma,
  • Süleyman Ergün,
  • Christoph Maack,
  • Srikanth Karnati,
  • Jan Dudek

摘要

Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (Taz), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in Taz deteriorate mitochondrial respiration, Ca2+-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with Taz-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in Taz-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in Taz-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in Taz-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with Taz-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac Taz-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in Taz-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.