TY - JOUR
T1 - Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish
AU - Sokol, Anna M.
AU - Uszczynska-Ratajczak, Barbara
AU - Collins, Michelle M.
AU - Bazala, Michal
AU - Topf, Ulrike
AU - Lundegaard, Pia R.
AU - Sugunan, Sreedevi
AU - Guenther, Stefan
AU - Kuenne, Carsten
AU - Graumann, Johannes
AU - Chan, Sherine S. L.
AU - Stainier, Didier Y. R.
AU - Chacinska, Agnieszka
PY - 2018/11
Y1 - 2018/11
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pgen.1007743
DO - 10.1371/journal.pgen.1007743
M3 - Journal article
VL - 14
SP - e1007743
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 11
ER -