Modelling of BCS1L-related human mitochondrial disease in Drosophila melanogaster

J Mol Med (Berl). 2021 Oct;99(10):1471-1485. doi: 10.1007/s00109-021-02110-1. Epub 2021 Jul 17.

Abstract

Mutations in BCS1L are the most frequent cause of human mitochondrial disease linked to complex III deficiency. Different forms of BCS1L-related diseases and more than 20 pathogenic alleles have been reported to date. Clinical symptoms are highly heterogenous, and multisystem involvement is often present, with liver and brain being the most frequently affected organs. BCS1L encodes a mitochondrial AAA + -family member with essential roles in the latest steps in the biogenesis of mitochondrial respiratory chain complex III. Since Bcs1 has been investigated mostly in yeast and mammals, its function in invertebrates remains largely unknown. Here, we describe the phenotypical, biochemical and metabolic consequences of Bcs1 genetic manipulation in Drosophila melanogaster. Our data demonstrate the fundamental role of Bcs1 in complex III biogenesis in invertebrates and provide novel, reliable models for BCS1L-related human mitochondrial diseases. These models recapitulate several features of the human disorders, collectively pointing to a crucial role of Bcs1 and, in turn, of complex III, in development, organismal fitness and physiology of several tissues.

Keywords: BCS1L; Drosophila melanogaster; Mitochondrial disease; Mitochondrial respiratory chain; Respiratory chain complex III.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • Amino Acid Sequence
  • Animals
  • Drosophila melanogaster / genetics*
  • Electron Transport Complex III / genetics*
  • Humans
  • Mitochondria / genetics*
  • Mitochondrial Diseases / genetics*
  • Molecular Chaperones / genetics
  • Mutation / genetics*

Substances

  • BCS1L protein, human
  • Molecular Chaperones
  • ATPases Associated with Diverse Cellular Activities
  • Electron Transport Complex III