Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish

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Dokumenter

Anna M. Sokol, Barbara Uszczynska-Ratajczak, Michelle M. Collins, Michal Bazala, Ulrike Topf, Pia R. Lundegaard, Sreedevi Sugunan, Stefan Guenther, Carsten Kuenne, Johannes Graumann, Sherine S. L. Chan, Didier Y. R. Stainier, Agnieszka Chacinska

Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life-essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases.
OriginalsprogEngelsk
TidsskriftPLOS Genetics
Vol/bind14
Udgave nummer11
Sider (fra-til)e1007743
Antal sider29
ISSN1553-7404
DOI
StatusUdgivet - nov. 2018

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