Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders

Nat Commun. 2014 Dec 18;5:5585. doi: 10.1038/ncomms6585.

Abstract

Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology
  • Cell Nucleus / metabolism
  • Databases, Pharmaceutical
  • Drug Repositioning
  • Gene Expression Regulation
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Diseases / drug therapy
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / pathology
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proton-Translocating ATPases / deficiency
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Molecular Targeted Therapy
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidative Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Pyridines / pharmacology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Thiones / pharmacology

Substances

  • Antifungal Agents
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Nuclear Proteins
  • Pyridines
  • Saccharomyces cerevisiae Proteins
  • TIM23 protein, S cerevisiae
  • TIMM23 protein, human
  • Thiones
  • pyrithione
  • Mitochondrial Proton-Translocating ATPases