Mitochondrial diseases caused by dysfunctional mitochondrial protein import

Abstract

Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

“…Novel pathogenic mechanisms involving mitochondria are currently discovered across all medical disciplines, including oncology, neurology, cardiology and immunology [ 171 , 172 , 173 , 174 ]. Investigations on mechanisms that affect the functions of TOM70 can take advantage of the fact that TOM70 and the associated protein import machinery are highly conserved from yeast to humans [ 52 ] ( Table 2 ).…”

The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins

“…Dysfunction of mitochondria is associated with many pathologies, including cancer, diabetes, and neurodegenerative disease. Mitochondrial diseases are genetic disorders that arise due to defective ATP production within the mitochondrion Jackson et al, 2018). Mitochondria require >1500 nuclear-encoded proteins to function; these proteins are delivered to specific mitochondrial sub-compartments (outer membrane; intermembrane space, inner membrane and matrix) by translocation and sorting machineries (Wiedemann and Pfanner, 2017).…”

“…Mitochondria require >1500 nuclear-encoded proteins to function; these proteins are delivered to specific mitochondrial sub-compartments (outer membrane; intermembrane space, inner membrane and matrix) by translocation and sorting machineries (Wiedemann and Pfanner, 2017). Mutations in genes encoding various subunits of mitochondrial translocation machineries have been linked to a number of distinct mitochondrial diseases (Jackson et al, 2018).…”

Split Intein-Mediated Protein Ligation for detecting protein-protein interactions and their inhibition

“…We further tested this by examining mitochondrial PPIs with SIMPL as mitochondria are special organelles with distinct features and their PPIs are often difficult to study. We selected several well-studied mitochondrial PPIs for this purpose ( Supplementary Table 4), including proteins involved in oxidative phosphorylation 28 , transport 29 , cristea organization 30 , and metabolism 31 . Baits were prepared using the IN format to avoid interference of transit peptides usually at N-termini of mitochondrial proteins.…”