Quantitative 3D Mapping of the Human Skeletal Muscle Mitochondrial Network

Abstract

SUMMARY Genetic 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.

Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

“…In fact, we previously showed that AX positively regulated insulin signaling and enhanced glucose uptake in differentiated L6 myotubes . On the other hand, AX has been shown to be of potential therapeutic usefulness for the prevention and treatment of insulin resistance in the liver through reducing oxidative stress and inflammation, and thereby to be useful for the prevention of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma . However, it is still unclear whether these effects of AX are attributable to its antiinflammatory effects mediated by its antioxidant activity.…”

Daily mitochondrial dynamics in cone photoreceptors

“…To examine individual mitochondrial morphology, manual segmentation was performed for a subset of cells imaged with SBFSEM ( Figure 1B, Video 1). Surface area and volume of each mitochondrion was used to calculate mitochondrial complexity index (MCI), a size-insensitive measure of morphological complexity (Vincent et al 2019). Mitochondria within clusters were heterogeneous in volume and MCI (Figure 2A), and MCI was poorly correlated with volume ( Figure 2B).…”

The structural basis for intermitochondrial communications is fundamentally different in cardiac and skeletal muscle

“…Three‐dimensional reconstructions of mitochondria in human muscles have revealed the presence of numerous connections between mitochondria via narrow ducts or pathways that directly join one mitochondrion to another (Vincent et al., ). We propose that the origin of these connecting structures and their ultrastructural details are different from those of nanotunnels; therefore, for clarity we propose to restrict the term nanotunnels to the structures specific to cardiac mitochondria and to use alternative names for other intermitochondrial connections, e.g.…”

“…Some instances of connecting ducts have been detected in skeletal muscle, often associated with evidence of severe structural alterations. The direct roles of such structures in the physiology and pathology of muscle are not well defined, because they occur in a variety of pathological conditions (Vincent et al., ; Vincent, Turnbull, Eisner, Hajnoczky, & Picard, ) and may also be present as part of the normal network of mitochondria (Vincent et al., ).…”