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

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

doi:10.1371/journal.pgen.1007743

Abstract

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.

Highlights

Mitochondria are important organelles with multiple cellular functions, serving as energy- and biosynthetic centres, participating in Ca2+ signalling and cell stress responses, and executing cell death
As mitochondria play various roles in cellular and tissue-specific contexts, the symptoms of mitochondrial pathologies can differ between patients
We investigated the role of mitochondrial biogenesis in vertebrate development by compromising the Mitochondrial Intermembrane space and Assembly (MIA) pathway in Danio rerio

Summary

Introduction

Mitochondria are important organelles with multiple cellular functions, serving as energy- and biosynthetic centres, participating in Ca2+ signalling and cell stress responses, and executing cell death. A group of genetically inherited diseases that are relatively rare but present devastating symptoms include encephalomyopathies, Leber’s Hereditary Optic Neuropathy (LHON), Leigh Syndrome and Barth Syndrome [1,2,3]. Another group of pathologies relate to more common, age-related and genetically predisposed conditions. Given that mitochondria orchestrate cellular metabolism, pathological conditions with symptoms of altered metabolism, including diabetes, obesity, cancer, as well as aging processes, have been associated with mitochondrial dysfunction [7, 8]. It underlines the necessity to generate new tools and models to study the molecular, cellular and organ related consequences of mitochondrial malfunction in complex organisms

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