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bioRxiv · 10.1101/2022.03.22.485341

3D Reconstructions of Mouse Skeletal Muscle and Heart Muscle Reveal a Decrease in the MICOS Complex and Altered Mitochondrial Networks

Vue, Z.·Lopez, E. G.·Neikirk, K.·Vang, L.·Beasley, H.·Marshall, A.·Hinton, A.
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Abstract

BackgroundDuring aging, muscle gradually undergoes loss of function including sarcopenia, losing mass, strength, endurance, and oxidative capacity. While mitochondrial aging is associated with decreased mitochondrial capacity, the genes associated with morphological changes in mitochondria during aging still require further elucidation. Furthermore, it is not completely understood how 3D mitochondrial structures are altered during aging in skeletal muscle and cardiac tissues. MethodsWe measured changes in mitochondrial morphology and mitochondrial complexity during the aging of murine gastrocnemius, soleus, and cardiac tissues using serial block face- scanning electron microscopy and 3D reconstruction. Lipidomic and metabolomic analysis elucidated concomitant changes associated with aging. We also used qPCR, transmission electron microscopy quantification, Seahorse Analyzer, and metabolomics to evaluate changes in mitochondria morphology and function upon loss of the MICOS complex. ResultsWe identified significant changes in 3D mitochondrial size and network configuration in murine gastrocnemius, soleus, and cardiac tissue during aging. These changes were concomitant with loss of mitochondria contact site and cristae organizing system (MICOS) gene expression during aging. Mitochondrial morphology was similar between aged mice and young mice. We show an age-related loss of the MICOS complex (Chchd3, chchd6, and Mitofilin) while their knockout results in alterations in mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we perform cellular metabolic profiling of young and aged tissues. Metabolomics and lipidomics showed profound alterations, including in membrane integrity, that support our observations of age-related changes in these muscle tissues. DiscussionIn tandem, our data suggest a relationship between the MICOS complex and aging, which could be linked to disease states with further 3D reconstruction studies. Our study highlights the importance of understanding tissue-dependent 3D mitochondrial phenotypical changes which occur across aging with evolutionary conservation between Drosophila and murine models. Graphical Abstract

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Vue, Z., Lopez, E. G., Neikirk, K., Vang, L., Beasley, H., Marshall, A., Hinton, A.. 2022-03-23. 3D Reconstructions of Mouse Skeletal Muscle and Heart Muscle Reveal a Decrease in the MICOS Complex and Altered Mitochondrial Networks. https://doi.org/10.1101/2022.03.22.485341

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