RT info:eu-repo/semantics/doctoralThesis
T1 Modulating Ca2+ homeostasis to counteract mitochondrial Complex-I deficiency in a rotenone-induced Caenorhabditis elegans model
A1 Romero Sanz, Silvia
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Biología molecular
K1 Complex I deficiency
K1 Disfunción del Complejo I
K1 Mitochondria
K1 Mitocondria
K1 Caenorhabditis elegans
K1 Calcio
K1 2302 Bioquímica
AB Despite the primary role of mitochondria in ATP production, this organelle also functions as a processor of cell. They integrate cellular signals and convert them into genetic programs that reorganize metabolic pathways and drive adaptive behaviours, enabling cells to respond to environmental demands. Dysfunctions in mitochondrial activity are strongly associated with a wide range of human diseases. Among them, Complex I (C-I) deficiency is one of the most prevalent mitochondrial disorders in childhood. It results in a heterogeneous group of clinical manifestations without a clear genotype–phenotype correlation and currently lacks effective therapeutic strategies. However, patient-derived fibroblasts consistently display common biochemical features, including increased reactive oxygen species (ROS) production, loss of mitochondrial membrane potential (Δψm), impaired ATP synthesis, and altered Ca²⁺ signalling. However, the molecular mechanisms driving disease progression remain unclear, and available treatments are limited to symptomatic management and general support of mitochondrial function.In this thesis, we developed and validated a rotenone-induced C-I deficiency model in Caenorhabditis elegans, which recapitulates major hallmarks of mitochondrial dysfunction while allowing the assessment of systemic and behavioural consequences. Using this model, we tested the hypothesis that modulation of Ca²⁺ signalling can influence the cellular response to C-I dysfunction. Our findings show that inhibition of the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) by CGP37157 provides partial protection by preserving mitochondrial health and improving locomotion, pharyngeal activity, and learning behaviour. Although dopamine levels were not restored, dopaminergic function was partially recovered. Moreover, partial knockdown of the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA in mammals, SCA-1 in C. elegans) also conferred protection, improving mitochondrial functionality and morphology, muscular activity, and dopaminergic-associated functions.Collectively, our results demonstrate that modulation of Ca²⁺ signalling constitutes a promising strategy to ameliorate the effects of C-I deficiency.
YR 2025
FD 2025
LK https://uvadoc.uva.es/handle/10324/80953
UL https://uvadoc.uva.es/handle/10324/80953
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 12-ene-2026