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Three-dimensional mitochondria reconstructions of murine cardiac muscle changes in size across aging


Vue Z , Neikirk K , Vang L , Garza-Lopez E , Christensen AT , Shao J , Lam J , Beasley KH , Marshall GA , Crabtree A , Anudokem Jr J , Rodriguez B , Kirk B , Bacevac S , Barongan T , Shao B , Stephens CD , Kabugi K , Koh H , Koh A , Evans SC , Taylor B , Reddy K A , Miller-Fleming T , Actkins VK , Zaganjor E , Daneshgar N , Murray AS , Mobley CB , Damo MS , Gaddy AJ , Riggs B , Wanjalla C , Kirabo A , McReynolds M , Gomez AJ , Phillips AM , Exil V , Dai D , Hinton Jr A . American Journal of Physiology-Heart and Circulatory Physiology. 2023 11 1; ().


With sparse treatment options, cardiac disease remains a significant cause of death among humans. As a person ages, mitochondria breakdown and the heart becomes less efficient. Heart failure is linked to many mitochondria-associated processes, including endoplasmic reticulum stress, mitochondrial bioenergetics, insulin signaling, autophagy, and oxidative stress. The roles of key mitochondrial complexes that dictate the ultrastructure, such as the mitochondrial contact site and cristae organizing system (MICOS), in aging cardiac muscle are poorly understood. To better understand the cause of age-related alteration in mitochondrial structure in cardiac muscle, we used transmission electron microscopy (TEM) and serial block facing-scanning electron microscopy (SBF-SEM) to quantitatively analyze the three-dimensional (3-D) networks in cardiac muscle samples of male mice at aging intervals of 3 mo, 1 yr, and 2 yr. Here, we present the loss of cristae morphology, the inner folds of the mitochondria, across age. In conjunction with this, the three-dimensional (3-D) volume of mitochondria decreased. These findings mimicked observed phenotypes in murine cardiac fibroblasts with CRISPR/Cas9 knockout of Mitofilin, Chchd3, Chchd6 (some members of the MICOS complex), and Opa1, which showed poorer oxidative consumption rate and mitochondria with decreased mitochondrial length and volume. In combination, these data show the need to explore if loss of the MICOS complex in the heart may be involved in age-associated mitochondrial and cristae structural changes.NEW & NOTEWORTHY This article shows how mitochondria in murine cardiac changes, importantly elucidating age-related changes. It also is the first to show that the MICOS complex may play a role in outer membrane mitochondrial structure.