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Age‐Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics

Steve D Guzman,P. Fraczek,Klimentini Itsani,Esraa K Furati,Devin Juros,Grace Kenney,Gregorio Valdez,Joe V. Chakkalakal,C. Aguilar

Published 2026 in Aging Cell

ABSTRACT

Age‐associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old‐aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single‐nucleus RNA sequencing before and after sciatic nerve crush from young and old‐aged muscles further revealed that sub‐synaptic myonuclei in old‐aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle‐specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10—two nuclear‐encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old‐aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub‐synaptic myonuclei using single‐nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain‐containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

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