Mitochondrial Ca²⁺ influx via MCU-1 Mediates PDR-1/Parkin Deficiency-Induced Muscle Dysfunction in <em>Caenorhabditis elegans</em>

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Parkinson’s disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, an organism that lacks muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial quality, redox homeostasis, and motor function, independent of neuronal degeneration. Silencing of pdr-1 mitigated age‑related mitochondrial fragmentation in body wall muscle cells. However, it resulted in impairments in locomotor activity and loss of nuclear GFP signals, particularly at later time points, indicating progressive muscle cell damage. In pdr-1-silenced animals, mitochondrial reactive oxygen species (mtROS) levels were elevated and mitochondrial membrane potential (ΔΨm) was reduced by day 2 of adulthood, well before the onset of motor decline, suggesting early oxidative mitochondrial dysfunction. In vivo imaging directly revealed elevated mitochondrial Ca2+ concentrations in pdr-1-deficient muscle cells. Furthermore, the elevation of mtROS and reduction of ΔΨm induced by pdr-1 silencing were abolished in mcu‑1 mutants, indicating that these defects require mitochondrial Ca²⁺ influx via MCU‑1. These findings demonstrate that mitochondrial Ca²⁺ overload via MCU-1 is an early upstream event in mitophagy-associated muscle dysfunction.

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