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<p>Mitochondrial transplantation (MT) is a promising therapeutic approach for the treatment of several pathologies, including ischemia-reperfusion injury (IRI). However, its efficacy remains limited by the high calcium concentration of the transplantation milieu. Elevated extracellular calcium induces MCU-mediated matrix calcium overload, leading to the opening of the permeability transition pore and metabolic collapse of the transplanted organelles. We hypothesized that shielding mitochondria from the adverse effects of high calcium using the reversible MCU inhibitor, Ru265, would increase the efficacy of MT therapy. An acute, non-invasive hindlimb skeletal muscle IRI model was established in BALB/c mice using orthodontic rubber bands to mimic peripheral artery disease. Isolated liver mitochondria were treated with Ru265 and evaluated for their responsiveness to calcium using the mitochondrial swelling assay. Mice subjected to hindlimb IRI received either standard MT (Mitochondria alone) or Ru265-treated mitochondria (Mito + Ru), and treatment efficacy was evaluated using various parameters. IRI induced significant changes in mouse body weight, musculoskeletal dysfunction, systemic inflammation, lipid peroxidation, and skeletal muscle damage. While standard MT therapy provided baseline recovery, the Mito + Ru group demonstrated superior outcomes, including significant body weight recovery, reduced infarct size, and attenuated oxidative stress. Thus, reversible shielding of exogenous mitochondria from calcium stress using Ru265 enhances the efficacy of MT therapy in rodent skeletal muscle IRI.</p>

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Transplantation of Ru265-treated mitochondria enhances the therapeutic impact on skeletal muscle ischemia-reperfusion injury

  • 期刊论文

  • 发表日期：

    2026年5月4日

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  • Saima Barki,
  • Fazal Wahid,
  • Shafia Khan,
  • Laiba Tariq Abbasi,
  • Zarrish Rubab,
  • Ameer Hamza,
  • Farman Ullah,
  • Khadeeja Ahsan,
  • Durre Shehwar,
  • Muhammad Rizwan Alam

摘要

Mitochondrial transplantation (MT) is a promising therapeutic approach for the treatment of several pathologies, including ischemia-reperfusion injury (IRI). However, its efficacy remains limited by the high calcium concentration of the transplantation milieu. Elevated extracellular calcium induces MCU-mediated matrix calcium overload, leading to the opening of the permeability transition pore and metabolic collapse of the transplanted organelles. We hypothesized that shielding mitochondria from the adverse effects of high calcium using the reversible MCU inhibitor, Ru265, would increase the efficacy of MT therapy. An acute, non-invasive hindlimb skeletal muscle IRI model was established in BALB/c mice using orthodontic rubber bands to mimic peripheral artery disease. Isolated liver mitochondria were treated with Ru265 and evaluated for their responsiveness to calcium using the mitochondrial swelling assay. Mice subjected to hindlimb IRI received either standard MT (Mitochondria alone) or Ru265-treated mitochondria (Mito + Ru), and treatment efficacy was evaluated using various parameters. IRI induced significant changes in mouse body weight, musculoskeletal dysfunction, systemic inflammation, lipid peroxidation, and skeletal muscle damage. While standard MT therapy provided baseline recovery, the Mito + Ru group demonstrated superior outcomes, including significant body weight recovery, reduced infarct size, and attenuated oxidative stress. Thus, reversible shielding of exogenous mitochondria from calcium stress using Ru265 enhances the efficacy of MT therapy in rodent skeletal muscle IRI.