Abstract
SUMMARYGenetic and biochemical defects of mitochondrial function are a major cause of human disease, but their link to mitochondrial morphology in situ has not been defined. Here, we develop a quantitative three-dimensional approach to map mitochondrial network organization in human muscle at electron microscopy resolution. We establish morphological differences between human and mouse and among patients with mitochondrial DNA (mtDNA) diseases compared to healthy controls. We also define the ultrastructure and prevalence of mitochondrial nanotunnels, which exist as either free-ended or connecting membrane protrusions across non-adjacent mitochondria. A multivariate model integrating mitochondrial volume, morphological complexity, and branching anisotropy computed across individual mitochondria and mitochondrial populations identifies increased proportion of simple mitochondria and nanotunnels as a discriminant signature of mitochondrial stress. Overall, these data define the nature of the mitochondrial network in human muscle, quantify human-mouse differences, and suggest potential morphological markers of mitochondrial dysfunction in human tissues.
Highlights
Mitochondria are multifunctional organelles that dynamically transition from punctate structures to branched elongated tubules within cells
We provide quantitative analysis of mitochondrial morphology in human muscle, perform a comparative mousehuman analysis, and evaluate the effect of mitochondrial DNA (mtDNA) mutations in patients with genetically confirmed primary mtDNA mutations on morphological parameters
Because our objective was to establish the morphology of individual mitochondria within the skeletal muscle network, we opted for a method with sufficient resolution to resolve closely juxtaposed membranes, which is critical to avoid merging immediately adjacent organelles with distinct outer mitochondrial membranes (Figure S1)
Summary
Mitochondria are multifunctional organelles that dynamically transition from punctate structures to branched elongated tubules within cells. Changes in mitochondrial shape in isolated cellular systems occur within minutes to hours and precede signaling events in model systems, influencing skeletal muscle atrophy (Romanello et al, 2010), oxidative stress (Shenouda et al, 2011; Yu et al, 2008), metabolic sensing (Ramırez et al, 2017; Schneeberger et al, 2013), and lifespan (Weir et al, 2017) This underscores the biological significance of mitochondrial morphology transitions for cellular and organismal functions (Eisner et al, 2018) and emphasizes the need to visualize and quantify mitochondrial shapes to gain insight into the relevance of mitochondrial morphology for human health and disease. This is salient in skeletal muscle, as subsequently described in mice (Eisner et al, 2014; Glancy et al, 2015; Leduc-Gaudet et al, 2015; Picard et al, 2013b), but the morphological 3D characteristics of human mitochondria have not been described
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