Dysfunctional mitochondrial Ca(2+) handling in mutant SOD1 mouse models of fALS: integration of findings from motor neuron somata and motor terminals

Abstract

Abundant evidence indicates that mitochondrial dysfunction and Ca(2+) dysregulation contribute to the muscle denervation and motor neuron death that occur in mouse models of familial amyotrophic lateral sclerosis (fALS). This perspective considers measurements of mitochondrial function and Ca(2+) handling made in both motor neuron somata and motor nerve terminals of SOD1-G93A mice at different disease stages. These complementary studies are integrated into a model of how mitochondrial dysfunction disrupts handling of stimulation-induced Ca(2+) loads in presymptomatic and end-stages of this disease. Also considered are possible mechanisms underlying the findings that some treatments that preserve motor neuron somata fail to postpone degeneration of motor axons and terminals.

Keywords: Ca2+ regulation; mitochondria; motor nerve terminal; motor neuron; mutant SOD1 models of fALS.

Figure 1

Diagrams summarizing aspects of mitochondrial handling of stimulation-induced Ca²⁺ loads in wild-type (B) and in presymptomatic (C) and symptomatic (D) SOD1-G93A motor neurons, inferred from measurements in somata and motor terminals. (A) Resting wild-type and SOD1-G93A motor neurons. ΔΨ_m is inside-negative due to H⁺ extrusion by the electron transport chain (ETC). Pi represents dynamic phosphate-dependent matrix Ca²⁺ buffering capacity. (B) Wild-type neuron buffering a large stimulation-induced Ca²⁺ influx. At least 50% of this influx enters mitochondria via the mitochondrial Ca²⁺ uniporter (MCU). The mitochondrial Ca²⁺ influx partially depolarizes ΔΨ_m, thus increasing ETC activity. Matrix Ca²⁺ buffering limits the increase in matrix [Ca²⁺]. (C) Presymptomatic SOD1-G93A neuron. Much of the incoming Ca²⁺ load continues to enter mitochondria. Matrix buffering persists, but the ability to accelerate ETC activity is reduced, so ΔΨ_m depolarization is greater. (D) Symptomatic SOD1-G93A neuron. Total mitochondrial Ca²⁺ uptake is reduced due to (1) greater depolarization of ΔΨ_m due to further reduction in the ability to accelerate ETC activity, (2) reduced ability to buffer matrix Ca²⁺, resulting in a greater elevation of matrix [Ca²⁺], even though total mitochondrial Ca²⁺ uptake is reduced. The greater elevation of matrix [Ca²⁺] produces transient openings of the mPTP. In all diagrams, CaB represents non-mitochondrial Ca²⁺ buffering/extrusion (including Ca²⁺ uptake by endoplasmic reticulum), which increases in symptomatic neurons as mitochondrial uptake diminishes. These simplified diagrams omit the outer mitochondrial membrane and the pH-dependence of the matrix Ca²⁺ buffer, and assume that the stimulation-induced Ca²⁺ influx across the cell membrane is not altered by the SOD1-G93A mutation.

Figure 2

Inhibiting SERCA pumps increases stimulation-induced changes in end-plate potential (EPP) amplitude in symptomatic SOD1-G93A mice (B) but not in wild-type mice (A). Horizontal bars indicate duration of action potential stimulation at 50 Hz. EPP amplitudes, recorded as in David and Barrett (2003), were normalized to their pre-tetanus value (EPP₀). 50 μM CPA.