Cardiolipin-deficient cells have decreased levels of the iron–sulfur biogenesis protein frataxin

• Published in: The Journal of biological chemistry Vol. 295; no. 33; pp. 11928 - 11937
• Main Authors: Li, Yiran, Lou, Wenjia, Grevel, Alexander, Böttinger, Lena, Liang, Zhuqing, Ji, Jiajia, Patil, Vinay A., Liu, Jenney, Ye, Cunqi, Hüttemann, Maik, Becker, Thomas, Greenberg, Miriam L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-08-2020; American Society for Biochemistry and Molecular Biology
• Subjects: Acyltransferases; Animals; Barth syndrome; Barth Syndrome - genetics; Barth Syndrome - metabolism; Barth Syndrome - pathology; cardiolipin; Cardiolipins - genetics; Cardiolipins - metabolism; Cell Line; Frataxin; Friedreich ataxia; Gene Deletion; Gene Knockout Techniques; iron; Iron - metabolism; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; iron–sulfur protein; Lipids; metal homeostasis; Mice; mitochondria; Myoblasts - metabolism; Myoblasts - pathology; phospholipid; protein import; tafazzin; Transcription Factors - genetics; Transcription Factors - metabolism; iron–sulfur protein; iron metabolism; Barth syndrome; mitochondria; metal homeostasis; iron; Friedreich ataxia; phospholipid; protein import; cardiolipin; tafazzin; frataxin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.013960

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin deficiency on iron homeostasis in the mouse myoblast model of BTHS tafazzin knockout (TAZ-KO) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron, as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron–sulfur cluster enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective iron–sulfur biogenesis. We observed decreased levels of Yfh1/frataxin, an essential component of the iron–sulfur biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in iron–sulfur biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.