Abstract
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease.
Highlights
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure
Skeletal muscle fibers contain large numbers of mitochondria classically known for their role in ATP synthesis through oxidative phosphorylation (OXPHOS), which fuels the energy-demanding process of muscle contraction[1,2]
We first performed a systematic review of the literature that identified 135 publications reporting EM findings in skeletal muscle biopsies of individuals with mitochondrial disease
Summary
Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. Research in recent decades has revealed that beyond energy production mitochondria perform a number of additional functions They contribute to Ca2+ homeostasis[3,4] and redox signalling[5,6], release pro-apoptotic factors regulating cell death[7], synthesize essential macromolecules including heme molecules[8], regulate nuclear gene expression[9,10], and can release immunogenic pro-inflammatory molecules into the cytoplasm and systemic circulation[11]. Previous investigations of mitochondrial ultrastructure in clinical samples were limited to standard (single-plane) transmission electron microscopy (TEM), precluding analysis of complex three-dimensional mitochondrial structures of potential functional significance
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