Calcium is reduced in presynaptic mitochondria of motor nerve terminals during neurotransmission in SMA mice.

Lopez-Manzaneda, Mario; Franco-Espin, Julio; Tejero, Rocio; Cano, Raquel; Tabares, Lucia

Lopez-Manzaneda, Mario; Franco-Espin, Julio; Tejero, Rocio; Cano, Raquel; Tabares, Lucia.

Afiliación

Lopez-Manzaneda M; Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
Franco-Espin J; Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
Tejero R; Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
Cano R; Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
Tabares L; Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.

Hum Mol Genet ; 30(8): 629-643, 2021 05 17.

Article en En | MEDLINE | ID: mdl-33693569

RESUMEN

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative motor neuron disease characterized by symmetrical muscle weakness and atrophy of limb and trunk muscles being the most severe genetic disease in children. In SMA mouse models, motor nerve terminals display neurotransmitter release reduction, endocytosis decrease and mitochondria alterations. The relationship between these changes is, however, not well understood. In the present study, we investigated whether the endocytosis impairment could be related to the functional alteration of the presynaptic mitochondria during action potential (AP) firing. To this aim, we generated a Synaptophysin-pHluorin (SypHy) transgenic mouse, crossed it with Taiwanese SMA mice, and recorded exo- and endocytosis and mitochondria Ca2+ signaling in real-time at ex vivo motor nerve terminals of Taiwanese-SypHy mice. The experiments were performed at the beginning of the motor symptoms to get an integrated view of the nerve terminal's functional state before degeneration. Our electrophysiological and live imaging results demonstrated that the mitochondria's capacity to increase matrix-free Ca2+ in SMA mice was significantly limited during nerve AP firing, except when the rate of Ca2+ entry to the cytosol was considerably reduced. These results indicate that both the mitochondrial Ca2+ signaling alterations and the secretion machinery defects are significant players in the dysfunction of the presynaptic terminal in SMA.

Asunto(s)

Calcio/metabolismo; Mitocondrias/metabolismo; Neuronas Motoras/fisiología; Atrofia Muscular Espinal/metabolismo; Terminales Presinápticos/metabolismo; Transmisión Sináptica/fisiología; Potenciales de Acción/genética; Potenciales de Acción/fisiología; Animales; Modelos Animales de Enfermedad; Endocitosis/genética; Endocitosis/fisiología; Proteínas Fluorescentes Verdes/genética; Proteínas Fluorescentes Verdes/metabolismo; Humanos; Ratones Transgénicos; Neuronas Motoras/metabolismo; Atrofia Muscular Espinal/genética; Atrofia Muscular Espinal/fisiopatología; Sinapsis/genética; Sinapsis/metabolismo; Sinapsis/fisiología; Sinaptofisina/genética; Sinaptofisina/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Calcio / Terminales Presinápticos / Transmisión Sináptica / Mitocondrias / Neuronas Motoras Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido

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