Quantitative 3D Mapping of the Human Skeletal Muscle Mitochondrial Network

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30018-X

Amy E. Vincent, Kathryn White, Tracey Davey, Jonathan Philips, R. Todd Ogden, Conor Lawess, Charlotte Warren, Matt G. Hall, Yi Shiau Ng, Gavin Falkous, Thomas Holden, David Deehan, Robert W. Taylor, Doug M. Turnbull,
and Martin Picard

• The authors investigate morphological differences of mitochondria in muscle between mice, humans and humans with mitochondrial disease.
• In all human and mouse muscle fibres analysed, the authors confirmed that the mitochondrial network is largely composed of distinct organelles, typically no more than a few microns in length. 
• The authors quantify "mitochondrial complexity" by taking the ratio of surface area to volume. Intuitively, a more "complex" organelle will have a higher surface area for a fixed volume, due to greater invagination. Naively taking the ratio yields a quantity with dimensions, so the authors raise the surface area to the power 3/2 to yield a dimensionless quantity. Phenomenologically, the authors find that squaring their metric increases its dynamic range. They name the resultant quantity the "mitochondrial complexity index" (MCI), which scales as MCI ~ SA^3/V^2 (SA=surface area, V=volume).
• The authors use a further metric, the "mitochondrial branching index" (MBI) which measured anisotropy. MBI > 1 denotes more branching in the transverse plane than the longitudinal direction of a muscle fibre. 
• The authors find that humans have smaller muscle mitochondria than mice, with comparable MCI.
• The authors found that, within cells, there is a large variability in mitochondrial volume and MCI (CV between 50-100%), although inter-cellular variability was smaller (CV < 50%). The authors also observed inter-individual variability in these metrics (CV ~ 50%).
• The authors studied a trio of genetically related patients carrying a tRNA-lys mutation at 40% (asymptomatic), 63% (mild myopathy) and 97% (severe myopathy). The patients with mild/severe myopathy had smaller mitochondria and lower MCI.
• Uncovering the correlation with single-cell heteroplasmy, respiratory chain function, and morphology remains a challenge for future studies.