The
outer mitochondrial membrane protein SLC25A46 has been recently
identified as a novel genetic cause of a wide spectrum of neurological
diseases. The aim of the present work was to elucidate the physiological
role of SLC25A46 through the identification of its interactome with
immunoprecipitation and proteomic analysis in whole cell extracts
from the cerebellum, cerebrum, heart, and thymus of transgenic mice
expressing ubiquitously SLC25A46-FLAG. Our analysis identified 371
novel putative interactors of SLC25A46 and confirmed 17 known ones.
A total of 79 co-immunoprecipitated proteins were common in two or
more tissues, mainly participating in mitochondrial activities such
as oxidative phosphorylation (OXPHOS) and ATP production, active transport
of ions or molecules, and the metabolism. Tissue-specific co-immunoprecipitated
proteins were enriched for synapse annotated proteins in the cerebellum
and cerebrum for metabolic processes in the heart and for nuclear
processes and proteasome in the thymus. Our proteomic approach confirmed
known mitochondrial interactors of SLC25A46 including MICOS complex
subunits and also OPA1 and VDACs, while we identified novel interactors
including the ADP/ATP translocases SLC25A4 and SLC25A5, subunits of
the OXPHOS complexes and F1Fo-ATP synthase,
and components of the mitochondria–ER contact sites. Our results
show that SLC25A46 interacts with a large number of proteins and protein
complexes involved in the mitochondria architecture, energy production,
and flux and also in inter-organellar contacts.
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