Autocatalytic pathways to cell death: A new analysis of the tuna burn problem

Abstract

During capture and storage of tuna, a small but significant number of fish display a characteristic muscle degeneration termed tuna burn. Based on detailed amino acid analyses and on previous studies of metabolite changes during online swimming of tuna, a new model of the etiology of burnt muscle is developed. According to this model oxygen-lack to white muscle (developing initially during capture) leads to a metabolic collapse, to a drop in ATP concentration, to a consequent opening of ATP-dependent K⁺ channels, with an efflux of K⁺, and thus to a collapse of membrane potential. When the membrane potential falls far enough to open voltage-dependent Ca⁺⁺ channels, Ca⁺⁺ influx occurs leading to elevated Ca⁺⁺ concentrations in the cytosol. This process is augmented by simultaneous movement of Ca⁺⁺ from sarcoplasmic reticulum (SR) and from mitochondria into the cytosol. At high intracellular concentrations Ca⁺⁺ can be devastating. One of its more notable effects involves the activation of Ca⁺⁺-dependent proteases, which preferentially target key components of the contractile machinery (troponins, tropomyosin, C-protein, M-protein, Z-discs, α-actinin) and thus cause disassembly of myofilaments prior to any significant hydrolysis of myosin or actin. This process is autocatalytic in the sense that Ca⁺⁺-activated proteases may act upon SR, thus increasing Na⁺ /Ca⁺⁺ exchange, and ultimately adding more Ca⁺⁺ to the cytosolic pool. According to this model, the difference between burnt and unburnt regions of the myotome is simply due to how far each region has moved along this self-destructive, autocatalytic pathway. The model is helpful in explaining previously perplexing data and in making useful (i.e. measurable) predictions for further studies of this important problem.