Forty years later: Mitochondria as therapeutic targets in muscle diseases

The hypothesis that mitochondrial dysfunction can be a general mechanism for cell death in muscle diseases is 40 years old. The key elements of the proposed pathogenetic sequence (cytosolic Ca2+ overload followed by excess mitochondrial Ca2+ uptake, functional and then structural damage of mitochondria, energy shortage, worsened elevation of cytosolic Ca2+ levels, hypercontracture of muscle fibers, cell necrosis) have been confirmed in amazing detail by subsequent work in a variety of models. The explicit implication of the hypothesis was that it “may provide the basis for a more rational treatment for some conditions even before their primary causes are known” (Wrogemann and Pena, 1976, Lancet, 1, 672–674). This prediction is being fulfilled, and the potential of mitochondria as pharmacological targets in muscle diseases may soon become a reality, particularly through inhibition of the mitochondrial permeability transition pore and its regulator cyclophilin D.