Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood

F.-Nora Vögtle1, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A. Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu19, Deepali N. Shinde, Ulrich Stephani, Johan L.K. Van Hove, Franz-Josef Müller, Ingo Helbig; The American Journal of Human Genetics , Volume 0 , Issue 0, n Press Corrected Proof DOI:10.1016/j.ajhg.2018.02.014

 The biological pathways that MPP is involved in are closely related to the more common neurological disease Friedreich’s ataxia, which is also actively studied by researchers at CHOP. In fact, frataxin, the protein altered in Friedreich’s ataxia, is one of the main targets of MPP. The conditions however, are very different, and the PMPCB-related disorders identified by Helbig and his collaborators are more severe than Friedreich’s ataxia.
Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts

Huihui Li, Hongting Zhao, Shuangying Hao, Longcheng Shang, Jing Wu, Chuanhui Song, Esther G. Meyron-Holtz, Tong Qiao & Kuanyu Li; Scientific Reportsvolume 8, Article number: 5118 (2018) doi:10.1038/s41598-018-23175-y

Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality.