Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans

Valenzuela-Villatoro, M.; de la Cruz-Ruiz, P.; Guerrero-Gomez, D.; Gomez-Orte, E.; Schiavi, A.; Maglioni, S.; Montero, M.; Fonteriz, R.; Casas-Martinez, J. C.; Briand, N.; Xu, J.; Rodriguez-Palero, M. J.; Artal-Sanz, M.; Olek, K.; Polaczyk, J.; Turek, M.; Pokrzywa, W.; Xu, S.; Irazoqui, J.; McDonagh, B.; Alvarez, J.; Olmedo, M.; Ventura, N.; Cabello, J.; Miranda-Vizuete, A.

doi:10.64898/2025.12.03.691999

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bioRxiv · 10.64898/2025.12.03.691999

Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans

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Abstract

Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis. HighlightsO_LIgsr-1a or trxr-2 single mutants have no overt phenotypes. C_LIO_LIgsr-1a trxr-2 double mutants are viable but show small size, gonad migration defects and reduced progeny. C_LIO_LILoss of both reductases in mitochondria triggers a constitutive ATFS-1-dependent UPRmt. C_LIO_LIATFS-1 is essential for gsr-1a trxr-2 worms survival. C_LIO_LIgsr-1a trxr-2 animals remodel mitochondrial morphology in a tissue-specific manner. C_LIO_LIgsr-1a trxr-2 double mutants exhibit impaired muscle and sperm function but enhanced wound healing. C_LI Graphical abstract (to be incorporated)

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Valenzuela-Villatoro, M., de la Cruz-Ruiz, P., Guerrero-Gomez, D., Gomez-Orte, E., Schiavi, A., Maglioni, S., Montero, M., Fonteriz, R., Casas-Martinez, J. C., Briand, N., Xu, J., Rodriguez-Palero, M. J., Artal-Sanz, M., Olek, K., Polaczyk, J., Turek, M., Pokrzywa, W., Xu, S., Irazoqui, J., McDonagh, B., Alvarez, J., Olmedo, M., Ventura, N., Cabello, J., Miranda-Vizuete, A.. 2025-12-05. Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans. https://doi.org/10.64898/2025.12.03.691999

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