Inner membrane fusion mediates spatial distribution of axonal mitochondria

Abstract

In eukaryotic cells, mitochondria form a dynamic interconnected network to respond to changing needs at different subcellular locations. A fundamental yet unanswered question regarding this network is whether, and if so how, local fusion and fission of individual mitochondria affect their global distribution. To address this question, we developed high-resolution computational image analysis techniques to examine the relations between mitochondrial fusion/fission and spatial distribution within the axon of Drosophila larval neurons. We found that stationary and moving mitochondria underwent fusion and fission regularly but followed different spatial distribution patterns and exhibited different morphology. Disruption of inner membrane fusion by knockdown of dOpa1, Drosophila Optic Atrophy 1, not only increased the spatial density of stationary and moving mitochondria but also changed their spatial distributions and morphology differentially. Knockdown of dOpa1 also impaired axonal transport of mitochondria. But the changed spatial distributions of mitochondria resulted primarily from disruption of inner membrane fusion because knockdown of Milton, a mitochondrial kinesin-1 adapter, caused similar transport velocity impairment but different spatial distributions. Together, our data reveals that stationary mitochondria within the axon interconnect with moving mitochondria through fusion and fission and that local inner membrane fusion between individual mitochondria mediates their global distribution.

Manipulation of Mitochondria Dynamics Reveals Separate Roles for Form and Function in Mitochondria Distribution

“…Morphology of mitoGFP-labeled neuronal mitochondria was evaluated within the cell bodies of ventral nerve cord neurons and segmental nerves of Drosophila third-instar larvae after expressing UAS-Marf-RNAi or UAS-Opa1-RNAi specifically in the nervous system using the elav-Gal4 driver. As expected (Debattisti et al, 2014;Sandoval et al, 2014;Yarosh et al, 2008;Yu et al, 2016), downregulation of either Marf or Opa1 causes distinct mitochondrial fragmentation. Fragmented mitochondria aggregate in the neuronal cell bodies of the ventral nerve cord ( Figure 1A) and appear fragmented along segmental nerves ( Figure 1B).…”

“…A growing body of evidence suggests that fusion and fission affect spatial distribution of mitochondria in neurons. Loss of Drp1, Marf/MFN, or Opa1 in Drosophila depletes mitochondria from neuromuscular junction synapses and motor axons (Sandoval et al, 2014;Verstreken et al, 2005;Yu et al, 2016). Mutations of the mitochondrial outer membrane fusion protein Mfn2 (Misko et al, 2012) or the inner membrane fusion protein Opa1 (Spinazzi et al, 2008) change the distribution of axonal mitochondria, and knockdown of Opa1 causes redistribution of dendritic mitochondria (Bertholet et al, 2013).…”

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects

“…Previous studies have linked deficiencies in mitochondrial trafficking to distal neurites in neurodegenerative diseases and neuropathies. 31,32 We observed that reduction of Vps13D in motoneurons led to strong impairment in the distribution of mitochondria in peripheral axons in segmental nerves and neuromuscular junction synapses (Fig 3). The density of mitochondria was progressively reduced concomitant with increased distance from the cell body locations in the central nervous system.…”

The role of mitochondria in axon development and regeneration

“…B). Both fission and fusion have been shown to occur along axons and axonal mitochondria are associated with the relevant molecular machinery (Amiri and Hollenbeck, ; Yu et al, ).…”