MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy

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.