Language
English
Publication Date
3-21-2024
Journal
Scientific Reports
DOI
10.1038/s41598-024-57340-3
PMID
38514795
PMCID
PMC10957967
PubMedCentral® Posted Date
3-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.
Keywords
Animals, Humans, Mice, Calcium, Calcium Channels, Cell Death, Mitochondria, Mitochondrial Membrane Transport Proteins, Muscular Dystrophy, Duchenne, Necrosis, Mitochondrial Proteins, Mechanisms of disease, Cardiovascular biology, Disease model
Published Open-Access
yes
Recommended Citation
Bround, Michael J; Abay, Eaman; Huo, Jiuzhou; et al., "MCU-Independent Ca2+ Uptake Mediates Mitochondrial Ca2+ Overload and Necrotic Cell Death in a Mouse Model of Duchenne Muscular Dystrophy" (2024). Faculty, Staff and Students Publications. 7984.
https://digitalcommons.library.tmc.edu/baylor_docs/7984