3D Reconstruction of Murine Mitochondria Exhibits Changes in Structure Across Aging Linked to the MICOS Complex
Authors: Vue Zer , Garza-Lopez Edgar , Neikirk Kit , Katti Prasanna , Vang Larry , Beasley Heather , Shao Jianqiang , Marshall Andrea G. , Crabtree Amber , Murphy Alexandria C. , Jenkins Brenita C. , Prasad Praveena , Evans Chantell , Taylor Brittany , Mungai Margaret , Killion Mason , Stephens Dominique , Christensen Trace A. , Lam Jacob , Rodriguez Benjamin , Phillips Mark A. , Daneshgar Nastaran , Koh Ho-Jin , Koh Alice , Davis Jamaine , Devine Nina , Muhammod Saleem , Scudese Estevão , Arnold Kenneth Ryan , Chavarin Valeria Vanessa , Robinson Ryan Daniel , Chakraborty Moumita , Gaddy Jennifer A. , Sweetwyne Mariya , Wilson Genesis , Zaganjor Elma , Kezos James , Dondi Cristiana , Reddy Anilkumar K. , Glancy Brian , Kirabo Annet , Quintana Anita M. , Dai Dao-Fu , Ocorr Karen , Murray Sandra A. , Damo Steven M. , Exil Vernat , Riggs Blake , Mobley Bret C. , Gomez Jose A. , McReynolds Melanie R. , Hinton Antentor 
Published: March 2022

Background

During 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.

Methods

We 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.

Results

We 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.

Discussion

In 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 betweenDrosophilaand murine models.

Graphical Abstract