Sakowska, P. | bioRxiv Science

bioRxiv2019

Mitochondria biogenesis in the synapse is supported by local translation

Synapses are the regions of the neuron that enable the transmission and propagation of action potentials on the cost of high energy consumption and elevated demand for mitochondrial ATP production. The rapid changes in local energetic requirements at dendritic spines imply the role of mitochondria in the maintenance of their homeostasis. Using global proteomic analysis supported with complementary experimental approaches, we show that an important pool of mitochondrial proteins is locally produced at the synapse indicating that mitochondrial biogenesis takes place locally to maintain the pool of functional mitochondria in axons and dendrites. Furthermore, we show that stimulation of synaptoneurosomes induces the local synthesis of mitochondrial proteins that are transported to the mitochondria and incorporated into the protein supercomplexes of the respiratory chain.\n\nSynopsis\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC=\"FIGDIR/small/789164v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (47K):\norg.highwire.dtl.DTLVardef@1813d6forg.highwire.dtl.DTLVardef@1e85cd3org.highwire.dtl.DTLVardef@2656f7org.highwire.dtl.DTLVardef@1177d7d_HPS_FORMAT_FIGEXP M_FIG Mitochondria biogenesis in the synapse is supported by local translation\n\nC_FIG O_LIMitochondrial proteins represent a large pool of proteins synthesized locally at the synapse\nC_LIO_LINewly synthesized mitochondrial proteins are imported into the mitochondria and incorporated into the respiratory chain complexes\nC_LIO_LIUncoupling of mitochondria and blocking mitochondrial import inhibits incorporation of de novo synthesized proteins into the mitochondrial protein complexes\nC_LI

neuroscience↗

bioRxiv2018

Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein, RESpiratory chain Assembly 1 (RESA1) factor, or cytochrome c oxidase assembly factor 7 (COA7) that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that RESA1 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS. We also found that pathogenic mutant versions of RESA1 are imported slower than the wild type protein, and mislocalized mutant proteins are degraded in the cytosol by proteasome machinery. Interestingly, proteasome inhibition rescued both the mitochondrial localization of mutant RESA1 and complex IV activity in patient-derived fibroblasts. We propose that proteasome inhibition is a novel therapeutic approach for a broad range of mitochondrial pathologies that are associated with the excessive degradation of mitochondrial proteins that is caused by genetic mutations or biogenesis defects.

biochemistry↗