Local translation in synaptic mitochondria influences synaptic transmission

Abstract

Mitochondria possess a small genome that codes for core subunits of the oxidative phosphorylation system, and whose expression is essential for energy production. Information on the regulation and spatial organization of mitochondrial gene expression in the cellular context has been difficult to obtain. Here we addressed this by devising an imaging approach to analyze mitochondrial translation, by following the incorporation of clickable non-canonical amino acids. We applied this method to multiple cell types, including hippocampal neurons, where we found ample evidence for mitochondrial translation in both dendrites and axons. Translation levels were surprisingly heterogeneous, were typically stronger in axons, and were independent of their distance from the cell soma, where mitochondria presumably descent from. Presynaptic mitochondrial translation correlated with local synaptic activity, and blocking mitochondria translation reduced synaptic function. Overall, these findings demonstrate that mitochondrial gene expression in neurons is intimately linked to neuronal function.

High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells

“…S5 ). In the future, to fully optimize the procedure and resolve all 13 polypeptides, it may be necessary to use gradient gel systems, as recently reported ( 36 ), and, to unambiguously assign all species, it will be important to use patient cell lines that carry defined mutations in each of the polypeptides.…”

Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease

“… 34 As a result, damaged synaptic mitochondria may be less amenable to retrograde transport and, therefore, depend on on-site repair via local translation of nuclear encoded mitochondrial transcripts. 35 Multiple nuclear-encoded mitochondrial mRNAs have indeed been found to be enriched at synapses, 36 including mRNA of cytochrome c oxidase subunit 4. In our data we found high positive correlation for genes encoding proteins of cytochrome c oxidase ( COX6A1 r PD = 0.45, COX6C r PD =0 .…”

Synapses: The Brain’s Energy-Demanding Sites

“…Despite the debate on the importance of astrocytic and neuronal glycolysis to fulfil energetic demands resultant from synaptic stimulation, it is generally accepted that OxPhos-driven ATP production is important to sustain synaptic stimulation in Drosophila neuromuscular junctions [ 66 ], hippocampal slices [ 53 ] and hippocampal neurons [ 37 , 38 , 67 ], as well as action potential stimulation in cortical neurons [ 40 ]. In accordance, translation of mitochondrial-encoded proteins is increased in active presynaptic hippocampal terminals [ 68 ] and in postsynaptic hippocampal terminals upon HFS [ 69 ]. Conversely, inhibition of mitochondrial translation decreased the amount of active synapses [ 45 ].…”