Morphological principles of neuronal mitochondria

Abstract

In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of functional outputs like ATP and heat often represent mitochondria as idealized geometries and therefore can miscalculate the metabolic fluxes. To analyze mitochondrial morphology in neurons of mouse cerebellum neuropil, 3D tracings of complete synaptic and axonal mitochondria were constructed using a database of serial TEM tomography images and converted to watertight meshes with minimal distortion of the original microscopy volumes with a granularity of 1.6 nanometer isotropic voxels. The resulting in silico representations were subsequently quantified by differential geometry methods in terms of the mean and Gaussian curvatures, surface areas, volumes, and membrane motifs, all of which can alter the metabolic output of the organelle. Finally, we identify structural motifs that are present across this population of mitochondria; observations which may contribute to future modeling studies of mitochondrial physiology and metabolism in neurons.

Extracting Mitochondrial Cristae Characteristics from 3D Focused Ion Beam Scanning Electron Microscopy Data

“…An indication of overall mitochondria shape is provided by the correlation between volume and surface area. In the population of mitochondria examined here, the relationship between mitochondrial volume and surface area is linear in accordance with a previous study of mouse cerebellum [16]. A curve representing the relationship between volume and surface area for a sphere has been added to the plot (fig.…”

“…Most often subsequent evaluation of crista proporties has been performed in 2D [11,12,13,10] and the validity of generalizations to 3D is questionable. Fortunately, studies of mitochondria and cristae in 3D based on manual reconstructions of individual mitochondria have also been performed for decades [14,15,16,17,18]. Mendelsohn Mitochondria are characterized by two membranes that define three functional compartments.…”

“…of magnitude [16] highlighting the importance of analyzing a larger population to ensure a representative sample. This becomes even more important for the dynamic mitochondrial cristae [19,20,21,22].…”

“…Most often subsequent evaluation of crista proporties has been performed in 2D [11, 12, 13, 10] and the validity of generalizations to 3D is questionable. Fortunately, studies of mitochondria and cristae in 3D based on manual reconstructions of individual mitochondria have also been performed for decades [14, 15, 16, 17, 18]. Mendelsohn et al 2021 evaluated 12 mitochondria and within this small sample the volume estimates varied by almost an order of magnitude [16] highlighting the importance of analyzing a larger population to ensure a representative sample.…”

Mitochondria morphology governs ATP production rate

“…For the amount of ATP synthases and ANTs considered in this work, no stochastic effects were evident (Supplementary Figure 4), only reducing the number of ATP synthases in the orders of 100s stochastic effects are appreciable (Supplementary Figure 5). Future efforts will likely involve simulations in spatially resolved geometries of mitochondria including realistic geometries [4, 27]. Thus, our model lays the foundation for future studies of the internal mitochondrial physiology and metabolism in cellular physiology.…”