Local mitochondrial replication in the periphery of neurons requires the eEF1A1 protein and thetranslation of nuclear-encoded proteins
Carlos Cardanho-Ramos,
Rúben Alves Simões,
Yi-Zhi Wang,
Andreia Faria-Pereira,
Ewa Bomba-Warczak,
Katleen Craessaerts,
Marco Spinazzi,
Jeffrey N. Savas,
Vanessa A. Morais
Affiliations
Carlos Cardanho-Ramos
Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Rúben Alves Simões
Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Yi-Zhi Wang
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Andreia Faria-Pereira
Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Ewa Bomba-Warczak
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Katleen Craessaerts
VIB Center for Brain and Disease Research and KU Leuven, Department of Neurosciences, Leuven, Belgium; Dementia Research Institute, University College London, London, UK
Marco Spinazzi
VIB Center for Brain and Disease Research and KU Leuven, Department of Neurosciences, Leuven, Belgium; Dementia Research Institute, University College London, London, UK; Neuromuscular Reference Center, Department of Neurology, Centre Hospitalier Universitaire d'Angers, Angers, France
Jeffrey N. Savas
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Vanessa A. Morais
Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Corresponding author
Summary: In neurons, it is commonly assumed that mitochondrial replication only occurs in the cell body, after which the mitochondria must travel to the neuron’s periphery. However, while mitochondrial DNA replication has been observed to occur away from the cell body, the specific mechanisms involved remain elusive. Using EdU-labelling in mouse primary neurons, we developed a tool to determine the mitochondrial replication rate. Taking of advantage of microfluidic devices, we confirmed that mitochondrial replication also occurs locally in the periphery of neurons. To achieve this, mitochondria require de novo nuclear-encoded, but not mitochondrial-encoded protein translation. Following a proteomic screen comparing synaptic with non-synaptic mitochondria, we identified two elongation factors – eEF1A1 and TUFM – that were upregulated in synaptic mitochondria. We found that mitochondrial replication is impaired upon the downregulation of eEF1A1, and this is particularly relevant in the periphery of neurons.
